CA2104793C - Pharmaceutical combination for the treatment of prostatic hyperplasia, containing a 5 alpha-reductase inhibitor and an antiandrogen - Google Patents

Abstract

Disclosed is an improved treatment for men with benign prostatic hyperplasia (BPH), involving combination therapy of a 5.alpha.-reductase inhibitor, e.g. a 17.beta.-substituted 4-azasteroid; a 17.beta.-substituted non-azasteroid, 17.beta.-acyl-3-carboxy-androst-3,5-diene, benzoylaminophenoxybutanoic acid derivative, fused benz(thio)amide or cinnamoylamide derivative, aromatic 1,2-diethers or thioethers, aromatic ortho acylaminophenoxy alkanoic acids, orthothioalkylacylaminophenoxy alkanoic acids, pharmaceutically acceptable salts and esters thereof, and particularly finasteride, in combination with an al-adrenergic receptor blocker, i.e., terazosin. The combination provides therapy at the molecular level for the underlying cause of the disease as well as providing symptomatic relief. Pharmaceutical compositions useful for treatment are also disclosed.

Description

BACKGROUND OF' THE INVENTION
1. Field of: the Invention This invention relates to a new method of treatment for patients, i.e. men having benign prostatic hyperplasia (BPH), involving combination therapy of administering therapeutically effective amount of a 5a-reductase inhibitor in combination with an al-adrenergic receptor bloc:ker .

2. Backqrotznd of the Invention Benign prostatic hyperplasia (BPH) affects a substantial number of males over the age of 50 and usually requ~_res surgery in advanced stages for relief.

It is known that testosterone (T) is secreted by the testes and adrenal glands but can undergo a. 5a-reductase mediated conversion to dihydrotes~tosterone (DHT) in peripheral sites including they liver, skin, and prostate. DHT is preferentially bound by the nucleus of prostatic cells thus indicating that DHT, rather than T, is the primary androgen required by the prostate for its growth and function. This led to the hypothesis that, by inhibiting 5a-reductase, the formation of DHT could be curtailed and hopefully prostate regression obtained.
Finasteride, 1713(N-t-butyl)carbamoyl-4-aza-5a-androst-1--en-3-one, was developed as a compound which was found to inhibit 5a-reductase and exhibit positive effects against benign prostatic hyperplasia.
Finasteride i.s a 4-azasteroid and a competitive, inhibitor of the enzyme. It shows no affinity for the androgen receptor and so would not be expected to 2o interf ere with the binding and action of T in those tissues, such as muscle, which respond to T, and thus should not result in f eminizing characteristics.
Typical 4-aza steroid 5a-reductase inhibitors include those developed by Merck. (See U.S. Pat. 4,.177,584 to Rasmusson, et al.; U.S. Pat.

4,220,735 to Rasmusson, et al.; U.S. Pat. 4,845,104 to Carlin, et: al.; U.S. Pat. 4,760,071 to Rasmusson, et al., which discloses finasteride, being 1713-(N-t-butyl)carbamoyl-4-aza-5a-androst-1-en-3-one, known by its trademark as PROSCAR*; U.S. Pat.
4,73,897 to Cainelli, et al.; U.S. Pat. 4,859,681 to Rasmusson, et al.; EPO Publn. 0 155 076; EPO
Publn. 0 004 949; and EPO Publn. 0 314 189.
SUBSTITUTE SHEET

2' 04793 In many instances, reversal of the prostate enlargement ~~rocess is accompanied by symptomatic relief from nocturi<~, hesitancy and difficulty in urination.
However, symptomatic relief does not occur in all cases.
When the 5a-:reductase inhibitor inhibits the rate of development of the enlarged prostate without attendant shrinkage, s~rrmptomatic relief as experienced by the patients may not occur.
Wh<~t is desired in the art is a combination therapy both to treat the underlying cause of BPH and to treat the short-term symptoms of the disease as well.
SUMMARY OF THE INVENTION
By this invention there is provided compositions and combinations for treating benign prostatic hy~~ertrophy patients being treated with a 4-aza steroid 5a-rcsductase inhibitor and experiencing inadequate s~rmptomatic relief, which compositions and combinations comprise a therapeutically effective amount of a 17(3-sub:~tituted 4-azasteroid, 5a-reductase inhibitor or a pharmaceutically acceptable salt or ester thereof, and an al-adrenergic receptor blocking agent, also termed herein ~~al-blocker~~ .
Thus, the combined effect of a 5a-reductase inhibitor in inhibiting DHT production in the prostate and the al-ad.renergic receptor blocker, e.g. terazosin, will result in a greater effect on suppressing the growth and symptomatic relief of enlarged prostate than either agent by itself.
A

In another aspect the invention provides the use of the 173-substituted 4-azasteroid and the al-adrenergic receptor blocker~in the treatment of benign prostatic hy~~erplasia.
In still another aspect of the invention there is provided use of the 173-substituted 4-azasteroid and the al-adrenergic receptor blocker in the manufacture of medicament for the treatment of benign prostatic hyperplasia.
BRIEF DESCRII?TION OF THE INVENTION
AND PREFERREI) EMBODIMENTS
In one preferred aspect, the present invention provides an e=ffective treatment of BPH in patients in need of symptomatic relief comprising therapeutically effective amounts of the al-blocker in association with the 5a-reduci:ase inhibitor or pharmaceutical composition thereof. The active compounds may be administered together or in any order, as discussed hereinafter.
By the term "patients in need of such treating"
is meant male patients with functioning gonads who are being treated with a 5a-reductase inhibitor in a therapeutic program designed to combat benign prostatic hyperplasia (BPH) and are discovered to be in need of symptomatic :relief .

2~ 04793 - 4a -The' use of therapeutically effective amounts of the 5a-reduct:ase inhibitor and the al-blocker in accordance w~_th this invention effectively treats the adverse symptoms of BPH including nocturia, hesitancy, decreased urinary flow and the like.
It has been shown that stimulation of a-adrenoreceptors contributes to the obstruction of benign prostatic hy~~erplasia (See M. Caine, et al., Br. J.
Urol . , Vol . 4E8, pp. 255-263 (1976) .
Alphas-adrenergic receptor blockers function generally as anti-hypertensive agents by blocking a-adrenergic receptor sites. They relax stromal (smooth) tissue in thE: bladder, which causes fibrous tissue to contract when stimulated by noradrenaline and results in decreased urinary flow rates. Thus, the effect of the al-blocker is to relax the fibrous tissue and result in increased urinary flow rates.

_S_ a-~~drenergic blocking agents bind selectively to the a class of adrenergic receptors and thereby interfere with the capacity of sympathomimetic amines to initiate actions at these sites.
There are prominent differences in the relative abilities of a-adrenergic blocking agents to antagonize the effects of sympathomemetic amines at the two subtypes of a receptors. It is known that Prazosin is much more potent in blocking al-(postsynaptic) receptors than a2-receptors that, among other effects, modulate neural release of transmitter (presumed presynaptic receptors).
Phenoxybenzamine is a moderately selective al-blocking agent, while phentolamine is only three to five times more potent in inhibiting al- than a2-adrenergic receptors. 7:n contrast, yohimbine is a selective az-blocker and has been shown to prevent the antihyperten~~ive effects of clonidine, an a2-agonist.
However, preferred in this invention are a-adrenergic b7.ockers which preferably are al-blockers and have little or no a2-blocking activity.

... '~ ~ ~~ '~~ ~~~'~~ ~'/US92/02258 G&: 1., . ~, ExamF~les of a-adrenergic receptor blockers are terazosin (Abbott-Hytrin*) whose chemical name is 1-(4-amino-6,7-dimethoxy-2-quinazo-linyl)-4-[(tetrahydro-2-furanyl)carbonyl]piperazine, as described in German Patent 2,646, 186 and U.S.
Patent 4,026,894; doxazosin (Pfizer-Cardura*) whose chemical name is 1-(4-amino-6,7-dimethoxy-2-quinazo-linyl)-4-[(2,3-dihydro-1,4-benzodioxin-2-yl)carbonyl]-piperazine, as described in German Patent 2,847,623 and U.S. Paten.t 4,18,390; prazosin (Pfizer-Minipres*) whose chemical name is 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-(2-furanylcarbonyl) piperazine, as described in British Patent 1,156,973, U.S. Patent 3,511,836 and Netherlands Patent Appln.
7,206,0b7; bunazosin (Sandoz-Detantol*) whose chemical name is 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)hexahydro 4-(1-oxobutyl)-1H-1,4-diazepine, as described in Belgian Pat. Appln.
806,626, U.S. Patent 3,920,636 and Japanese Kokai 75,140,474; indoramin (Baratol*-Wyeth) whose chemical name is N-[1-[2-(1H-indol-3-yl)ethyl]-4-piperidinyl]benzamide, as described in South African Patent 68 03204, U.S. Patent 3,527,761; Alfuzosin (Synthelabs) whose chemical name is N-[3-[(4-amino-6,7-dimethoxy-2-quinazolinyl)methylamino]propyl]
tetrahydro-2-furancarboxamide, as described in German Patent 2,904,445 and U.S. Patent 4,315,007.
Preferred is where the 4-aza steroid has the formula:
SUBSTITUTE SHEET

_ 7 _ p Ra C- NR~
R. , , K
I
p ~' H
R
wherein the dotted line represents a double bond when present, R1 and R3 are independently hydrogen, methyl or ethyl, R2 is a hydrocarbon radical selected from straight or branched chain substituted or unsubstituted alkyl, cycloalkyl, or aralkyl of from 1-12 carbons or monocyclic aryl optionally containing 1 or more lower alkyl substituents of from 1-2 carbon atoms and/or 1 or more halogen substituents, R' is hydrogen or methyl, R" is hydrogen or !3-methyl, R"' is hydrogen, a-methyl or !3-methyl, and pharmaceui:ically acceptable salts or esters thereof .
A preferred embodiment of the compound of formula I applicable in the process of our invention is represented by the formula:

C- NHRz II
i~H
R
SUBSTITUTE SHEET

'~~~~r~~~ - 8 -wherein R1 is hydrogen, methyl or ethyl, and R2 is branched chain alkyl cycloalkyl, aralkyl of from 4-12 carbons, phenyl, optionally substituted by methyl, chloro or fluoro, substituted or unsubstituted 1-, 2-adamantyl, 1-, 2-adamantyl-methyl, 1-, 2- or 7-norbornanyl, 1-, 2- or 7-norbornanymethyl.
Representative compounds of the present invention include the following:
1713-(N-tert-amylcarbamoyl-4-aza-5a-androst-1-en-3-one, 1713-(N-tert-hexylcarbamoyl)-4-aza-5a-androst-1-en-3-one.
1713-(N-tert-butylcarbamoyl)-4-aza-Sa-androst-1-en-3-one, 1713-(N-isobutylcarbamoyl)-4-aza-5a-androst-1-en-3-one, 173_(N-tert-octylcarbamoyl)-4-aza-Sa-androst-1-en-3-one, 1713-(N-octylcarbamoyl)-4-aza-5a-androst-1-en- 3-one, 1713-(N-1,1-diethylbutylcarbamoyl)-4-aza-Sa-androst-1-en-3-one, 1713-(N-neopentylcarbamoyl)-4-aza-Sa-androst-1-en-3-one, 1713-(N-2-adamantylcarbamoyl)-4-aza-Sa-androst-1-en-3-one, 1713-(N-1-adamantylcarbamoyl)-4-aza-Sa-androst-1-en-3-one, 1713-_(N-2-norbornylcarbamoyl)-4-aza-5a-androst-1-en-3-one, SUBSTITUTE SHEET

1713-(N-1-norbornylcarbamoyl)-4-aza-5a-androst-1-en-3-one, 1713-(N-phenylcarbamoyl)-4-aza-4-methyl-5a-androst-1-en-3-oms, 1713-(N-benzyl~~arbamoyl)-4-aza-4-methyl-5a-androst-1-en-3-once , 1713-(N-tert-amylcarbamoyl-4-aza-4-methyl-5a-androst-1-en-3-once , 1713-(N-tert-h~exylcarbamoyl)-4-aza-4-methyl-5a-androst-1~-en-3-one , 1713-(N-tert-b~itylcarbamoyl)-4-aza-4-methyl-5a-and rost-1~-en-3-one , 1713-(N-isobut:;~lcarbamoyl)-4-aza-4-methyl-5a-androst-1-en-3-ome, 17~-(N-tert-octylcarbamoyl)-4-aza-4-methyl-5a-androst-1~-en-3-one, 1713-(N-1,1,3,:3-tetramethylbutylcarbamoyl)-4-aza-5a-androst-1-en-3-one, 17f3-(N-octylc;~rbamoyl)-4-aza-4-methyl-5a-androst-1~-en-3-one, 1713-(N-1,1-di~ethylbutylcarbamoyl)-4-aza-4-methyl-5a-androst-1~-en-3-one, 1713-(N-neopentylcarbamoyl)-4-aza-4-methyl-5a-androst-1-en-3-on~e , 1713(N-1-adamantylcarbamoyl)-4-aza-5a-androstan-3-one;
17f3(N-1-adama;ntylcarbamoyl)-4-methyl-4-aza-5a-androst-1~-en-3-one;
1713(N-1-adama:ntylcarbamoyl)-4-methyl-4-aza-5a-androstan-3-one;
1713 ~ N-1-adam~antylmethylcarbamoyl)-4-aza-5a-androst-1~-en-3-one;
SUBSTITUTE SHEET

-lo-1713-(N-2-adamantylcarbamoyl)-4-aza-5a-androstan-3-one;
1713-(N-methyl-N-2-adamantylcarbamoyl)-4-methyl-4-aza-androstan-3-one;
1713-(N-2-adamantylcarbamoyl)-4-methyl-4-aza-5a-androstane-3-one;
1713-(N-2-adamantylcarbamoyl)-4-methyl-4-aza-5a-androst-1-en-3-one;
1713-(N-methyl-N-2-adamantyl)carbamoyl-4-methyl-4-aza-androst-1-en-3-one;
1713-(N-(3-methyl -1-adamantyl-carbamoyl)-4-aza-4-methyl-5a-androst-an-3-one;
1713-(N-exo-2-norbornanylcarbamoyl)-4-aza-4-methyl-5a-androst-1-en-3-one;
1713-(N-exo-2-norbornanylcarbamoyl)-4-aza-5a-androst-1-en-3-one;1713-(N-2-adamantylcarbamoyl)-4-aza-5a-androst-en-3-one;
1713-(N-methyl-N-2-adamantylcarbamoyl)-4-aza-4-methyl-androstan-3-one;
17f3-(N-2-adamantylcarbamoyl)-4-methyl-4-aza-5a-androstan-3-one; and 1713-(N-methyl-N-2-adamantyl)carbamoyl-4-methyl-4-aza-androst-1-en-3-one.
The corresponding compounds of those above wherein the 4-aza substitvent is substituted in each of the above named compounds with a hydrogen, methyl or an ethyl radical, to form a different N-substituent, and wherein a double bond can be optionally present as indicated by the dotted line in position 1.
SUBSTITUTE SHEET

The alkyl, cycloalkyl, aralkyl, monocyclic aryl, 1-, 2-adamantyl or 1-, 2-norbornanyl moieties can be substil:uted with one or more substi-tuents of the following: C1-C4 linear/branched alkyl, including methyl, ethyl, isopropyl, n-butyl; vitro;
oxo; C~-C9 aralkyl, including benzyl; (CH2)n COOR
where n is 0-.? and R is H or C1-C4 linear/branched alkyl including methyl, ethyl; CH20H; OH; OR where R is Cl-C4 linear/branched alkyl including methyl, ethyl; halo, :including fluoro, bromo, iodo; COOH;
COOR, where R is linear/branched C1-C4 alkyl;
-CONH2; CH2NH~,; CHZNHCOR where R is C1-C4 linear/
branched alky~L including methyl, ethyl; phenyl;
o, m, p-substituted phenyl including p-vitro, p-amino and p--sulfo; or cyano. The amino group of the adamantyl or norbornanyl moiety can also be substituted as R1 with methyl and ethyl, as well as hydrogen.
Also included within the scope of this invention are pharmaceutically acceptable salts or esters, where a basic or acidic group is present on the substitutead alkyl, cycloalkyl, aralkyl, adamantyl or norbornany7L moiety. When an acidic substituent is present, i.e. -COOH, there can be formed the ammonium, sodium, potassium, calcium salt, and the like, for use as the dosage form.
WherE~ a basic group is present, i.e. amino, acidic salts, i.e. hydrochloride, hydrobromide, acetate, pamoate, and the like, can be used as the 3o dosage form.
SUBSTITUTE SHEET

Also, in the case of the -COOH group being present, pharmaceutically acceptable esters can be employed, e.g. acetate, maleate, pivaloylogymethyl, and the like, and those esters known in the art for modifying solubility or hydrolysis characteristics for use as sustained release or prodrug formulations.
Representative examples include for R2 (where AD is adamantyl):
3, 5, 7-trinitro-1-AD; 4-oxo-1-AD; 1-benzyl-1-AD;
4,4-dimethyl-1-Ad; 3,7-dimethyl-5-carboxymethyl-1-AD;
3-carboxymethyl-1-AD; 3-chloro-1-AD; 1,3-dihydroxy-6,6-dimethyl-2-AD; 3-chloro-1-AD; 4-carbethoxy-2-AD;
4-carboxy-2-AD; 3-isopropyl-1-AD; 3-n-butyl-1-AD;
3-propyl-1-AD; 3-,5-diethyl-1-AD; 3-hydroxymethyl-1-AD; 2-carboxy-1-AD; 3-methyl-1-AD; 5-hydroxy-2-AD;
2-hydroxy-1-AD; 1-aminomethyl-1-hydrogy-2-AD;
2-oxo-1-AD; 2-phenyl-2-AD; 1-amino-methyl-2-AD;
1-carboxy-2-AD; 1-aminocarbonyl-2-AD; 3-hydroxy-5,7-dimethyl-1-AD; 4-fluoro-1-AD; 3-fluoro-1-AD;
4-hydroxy-2-AD; 3-phenyl-1-AD; 3-(p-aminophenyl)-1-AD; 3-(p-nitrophenyl)-1-AD; 3-methyl-5-hydroxymethyl-1-AD; 3,5-dimethyl-4-hydroxy-1-AD;
2-hydroxymethyl-2-AD; 3-<p-sulfophenyl)-1-AD; 3-methyl-5-ethyl-1-AD; 2-carboxy-2-AD; 3,5-7-trimethyl-1-~; 4-iodo-2-AD; 4-bromo-2-AD; 4-chloro-2-AD;
1-acetylaminomethyl-2-AD; 1-carboxymethyl-2-AD;
1-methyl-2-AD; 1-aminocarbogylmethyl-2-AD;
1-aminocarboxyl-1-AD; 2-cyano-2-AD; 3,5-dimethyl-7-ethyl-1-AD; 4-hydro$y-1-AD; 1-hydroxy-2-AD;
5-carboxy-3-methyl-1-AD; 3,5-dimethyl-7-carboxy-1-AD, 3-carboxy-1-AD; 3-hydroxy-1-AD; and the like.
SUBSTITUTE SHEET

W'°' 92/16213 PCT/US92/02258 Representative examples include f or R2 as substituted norbornanyl moieties are (where NB is norbornanyl):
2-NB; 1,7,7-tri;methyl-4-phenyl-2-NB; 3-carboxy-2-NB; 3-phenyl-2-carboxy-2-NB; 2-cyano-3-phenyl-2-NB;
3-hydroxy-4,7,7-trimethyl-2-NB; 6-hydroaymethyl-2-NB; 5-cyano-2-NB; 3-allyl-2-NB; 1-NB; 7,7-dimethyl-1-hydroxymethyl-2~-NB; 3-methoxy-4,7,7-trimethyl-2-NB;
3-aminocarbonyl~-2-NB; 3-ethoxycarbonyl-2-NB; 3,3-dimethyl-2-NB; 7-oxo-1-NB; 3-phenyl-2-NB; 1-carboxy-methyl-7,7-dimethyl-2-NB; 1-ethyl-2-NB; 1-methyl-2-NB; 2,2,3,3,5,5,6,6,7,7-decafluoro-1-NB; 3-hydroay-2-NB; 3-chloro-2-NB; 3-(p-methoxyphenyl)-Z=NB; 2,2-dimethyl-3-meth:;~lene-7-NB; 3-oxo-2-NB; 1-methoxy-2-Ng; 7-NB; 3-isopropyl-2-NB; 2-bromo-1-NB; 3-chloro-1-NB; and the hike.
Procedures for preparing the compounds of Formula I useful in this invention, including the above, are well known in the art.
The novel compounds of formula I of the present invention can be prepared by a method starting with the known steroid ester <IIIA) of the formula COOR
IIIA
I H
R
suBS~rrruTE sHEEr -..
~i~~~'~~~14 -1713-(carbomethoxy)-4-aza-S-a-androstan-3-ones which includes the stages of optionally 1) dehydrogenating said starting material to produce the corresponding compound containing a double-bond in the 1,2-position of the A-ring, 2) converting the 17-carbomethoxy substituent into an N-substituted alkyl, cycloalkyl, aralkyl, monocylic acyl, or adamantylcarbamoyl substituent and, if desired, 3) alkylating the A-ring nitrogen to introduce a N-methyl or N-ethyl substituent into the A ring 4-position. For the dehydrogenatin step, it is preferable that the 4-aza nitrogen be unsubstituted. The alternate pathways can consist of one or more discrete chemical steps and if desired can take place before step (1) or following step (1) or step (3).
In accordance with the process of the present invention (see flow sheet), the products of our invention are formed by optionally: (1) heating a 1713-alkoxycarbonyl-4-aza-5a-androstan-3-ones, com-pound III, (prepared in the literature as described in the ref erence US Patent 4,377,584) with a dehydro-genating agent such as benzeneseleninic anhydride in a refluxing inert solvent, e.g. chlorobenzene, to form a 1713-alkoxycarbonyl-4-aza-5a-androst-1-ene-3-one IV
(alternately, the dichlorodicyanobenzoquinone process of Dolling, et al., JACS 1988, Vol. 110, pp.
3318-3319, can be used); (2) the formed Sa-androst-1-en-3-one compound from Step 1 can be reacted with, e.g. sodium hydride under anhydrous conditions in a neutral solvent such as dimethylformamide; <3) con-tacting the resulting reaction mixture with an alkyl (methyl or ethyl) iodide to form the corresponding suss-rrruTE sHEEr 17-13-alkoxy-adamantyl-carbamoyl-4-alkyl-4-aza-5a-androst-1-en-:3-one V; (4) subsequently hydrolyzing said 17f3-alko:~ycarbonyl-4-alkyl-4-aza-5a-androst-1-en-3-one with a strong base, such as aqueous methanolic potassium hydroxide at the reflux temper-ature, followed by acidification and isolation- of the resulting ste:roidal acid to yield 1713-carboxy 4-alkyl-4-aza-5a-andr~~st-1-en-3-one VI; (5) said steroidal acid can be tlhen converted to its corresponding 2-pyridylthio ester by ref luxing with triphenyl phosphine and 2,2'-dipyridyl disulfide in an inert solvent such .as toluene and the resulting product 1713-(2-pyridylthiocarbonyl)-4-alkyl-4-aza-5a-androst-1-en-3-one VI:I can be isolated by chromatography on e.g. silica gel; and (6) said pyridylthio ester can be thenreacted with 1-adamantyl-, 2-adamantylamine or norbornanylamine in an inert solvent e.g. tetrahydro-furan, to form the desired product 1713-N-adamantyl-carbamoyl-4-alkyl-4-aza-5a-androst-1-en-3-one VIII
2o which can be isolated by chromatography e.g. on silica gel. When the previous reaction is carried out in the absence of first forming the double bond at position 1, the corresponding 17J3-(N-adamantyl-carbamoyl)-4-alkyl-4-aza-5a-androstan-3-one (or N-norbornanyl carbamoyl compound) is prepared.
In accordance with an alternate process of our invention the corresponding N-unsubstituted-1713(N-adamantyl-carbamoyl)-4-aza-5a-androst-1-en-3-one XIV
is readily prepared from the 1713 (alkoxycarbonyl)-3o 4-aza-5a-androstone-3-one IV by. repeating the above seriES of reaction steps but omitting the alkylation Step 2 herein above, i.e. treatment of the 4-aza-5-SUBSTITUTE SHEET

a-androst-1-en-3-one with e.g. sodium amide followed by methyl or ethyl iodide via intermediates XII and XIII.
In accordance with a further alternate process of preparing the compounds of our invention having only hydrogen as the sole substituent on the ring A - nitrogen, the double bond in the A ring is introduced as the last step of the process. Thus, a 17f3-alkoxycarbonyl 4-aza-5a-androstan-3-one III is hydrolyzed to the corresponding steroidal acid IX
1713-carboxy-4-aza-5a-androstan-3-one which in turn is converted to the corresponding pyridylthio ester, 17J3 (2-pyridylthiocarbonyl)-4-aza-5a-androstan-3-one, X
followed by treatment of the ester with an amine of formula R2-NH2 wherein R2 is as defined hereinabove as 1- or 2-adamantyl or 1-, 2-, or 7-norbornanyl to form a 1713 (N-adamantyl-carbamoyl)-4-aza-5a-androstone-3-one XI which is dehydrogenated as previously described to produce compound XIV, 173_(N-adamantyl-carbamoyl)-4-aza-androst-1-en-3-one or corresponding norbornanyl derivative.
In another alternate method of introducing the 1713-(N-adamantyl-carbamoyl)substituent ,into a 1713-carboxy androstane compound of formula VI, XII
or IX, each is treated in a manner similar to the procedure described in Steroids, Vol. 35 #3, March 1980, p. 1-7 with dicyclohexylcarbodiimide and 1-hydroxybenzo-triazole to form the 17J3-(1-benzo-triazoloxycarbonyl)-4-aza-5a-androst-1-en-3-one, VII, XIII or compound X, wherein the substituent X is benzotriazoloxy group.
SUBSTITUTE SHEET

'~~~4'~

The 16-methyl derivative wherein R~~~ is methyl are prepared from known 16-methyl-17-acyl-4-methyl-4-aza-5a-androstan-3-ones, e.g.
4,16(i-dimeth:girl-17~-acetyl-4-aza-5a-androstan-3-one by known dehydrogenation procedures f or 4-methyl-4-aza compounds to produce the corresponding 4,16~-dimeth~;~l-17~-acetyl-4-aza-5a-androst-1-en-3-one.
The above reactions are schematically represented in the following flowsheet.
l0 SUBSTITUTE SHEET

Flowsheet Co=cH, Co,Ct~ co,cH3 w ~~=v Iii O I H O I H O I H
CFi~ H H
l0 1 1 1 COOH COON COOH
i i -VI XII IX
O j O j O
t H I H I H
CHj H H
o . x . o ..
c-x C=o C-x vi I ~~~r~xm x O O O
C- R~ C- R~
i ~ i vIII xxv xz X is 2-pyridylthio or 1-benzotriazoloxy.
R2 is 1- or 2-adamantyl or norbornanyl.
SUBSTITUTE SHEET

Also preferred is where the 4-aza steroid has the formula:
17f3-acyl-4-aza-Sa-androst-1-eve-3-one compound of the formu7La:
\\ ~a C
R" ' R' '' ~~ R, , I A
II H
R
wherein the dotted line represents a double bond when present;
R is selected from hydrogen, methyl and ethyl;
R2 is (a) a monovalent radical selected from straight or branched chain alkyl, or cycloalkyl, of from 1-12 carbons, which can be substituted by one or more of C1-C2 alkyl or halo;
(b) an aralkyl radical selected from benzyl or phenethyl;
(c) a polycyclic aromatic radical which can be substituted with one or more of:
-OH, protected -OH, -OC1-C4 alkyl, C1-C4 alkyl, halo or vitro;
(d) a monocyclic aromatic radical which can be substituted with one or more of:
SUBSTITUTE SHEET

~10~'~~J
- Zo -(1) -OH, -OCl-C4 alkyl, C1-C4 alkyl, -(CH2)mOH, -(CH2)n, COOH, including protected hydroxy, where m is 1-4, n is 1-3, providing C1-C4 alkyl is only present when one of the above oxygen-containing radicals is present;
(2) -SH, -SCl-C4 alkyl, -SOCl-C4 alkyl, -S02C1-C4 alkyl, -S02N(Cl-C4-alkyl)2, Cl-C4 alkyl -(CHZ)mSH, -S-(CH2)n-0_ COCH3, where m is 1-4 n is 1-3, providing Cl-C4 alkyl is only present when one of the above sulfur containing radicals is present;
is (3) N(R3)2, which can be protected, where R3 is independently H or Cl-C4 alkyl, Where the monoaryl ring can also be further substituted with Cl-C4 alkyl;
and (4) heterocyclic radical selected from 2-or 4-pyridyl, 2-pyrrolyl, 2-furyl or thiophenyl;
and R~, R~~ and R~~~ are each selected from hydrogen and methyl, and pharmaceutically acceptable salts thereof .
A preferred embodiment of the compounds of our invention process is:
the compound of above Structure IA
SUBSTITUTE SHEET

wherein the dotted line is a double bond, R is hydrogen or methyl, and R2 is branched chain alkyl, or cycloalkyl of from 4-1~) carbons, and R~~ and R~~~ are hydrogen.
Anoi:her embodiment of the invention is the compounds of above Structure I where R2 is phenyl, or phenyl substituted by substituents described above, including where R2 is phenyl, 2-, 3-, or 4-tolyl, gylyl, 2-bromophenyl, 2-chlorophenyl, 2,6--dichlorophenyl, 2,6-dibromophenyl, aminophenyl, N-alkylaminophenyl, N-N-dialkyl-aminophenyl, 4-biphenyl, 3-biphenyl, naphthyl, anthracyl, phenanthryl, thiophenyl, methylthiophenyl, methylsulfinyl, phenyl, methylsulf ophenyl, aminosulfophenyl, thioethylphenyl, acet:oxymethylthiophenyl, 1713-~ ( 4-hyd roxyphenyl ) , 1713- ( 3-hyd roxyphenyl ) , 1713-~(3,4-dihydroxyphenyl), or 1713-(3,5-dime~thyl-4-hydroxyphenyl).
Representative compounds of the invention are:
1713-(phenylca~rbonyl)-4-aza-4-methyl-5a-androst-1-ene-3-one;
173-(2-tolylc.arbonyl)-4-aza-4-methyl-5a-androst-1-ene-3-one;
1713-(3-tolylcarbonyl)-4-aza-4-methyl-5a-androst-1-ene-3-one;
1713-(4-tolylcarbonyl)-4-aza-4-methyl-5a-androst-3 0 1-ene-3-one ;
1713-~2-bromophenylcarbonyl)-4-aza-4-methyl-5a-androst-1-ene-3-one;
SUBSTITUTE SHEET

~1~~~'1~~

1713-(2-chlorophenylcarbonyl)-4-aza-4-methyl-5a-androst-1-ene-3-one;
1713-(2,6-dichlorophenylcarbonyl)-4-aza-4-methyl-5a-androst-1-ene-3-one;
1713-(2,6-dibromophenylcarbonyl)-4-aza-4-methyl-5a-androst-1-ene-3-one;
1713-(xylylcarbonyl)-4-aza-4-methyl-5a-androst-1-ene-3-one;
1713-(t-butylcarbonyl)-4-aza-5a-androst-1-ene-3-one;
1713_(isobutylcarbonyl)-4-aza-5a-androst-1-ene-3-one;
1713-(isooctylcarbonyl)-4-aza-5a-androst-1-ene-3-one;
1713-(n-octylcarbonyl)-4-aza-5a-androst-1-ene-3-one;
1713-(1,1-diethylbutylcarbonyl)-4-aza-5a-androst-1-ene-3-one;
1713-(neopentylcarbonyl)-4-aza-5a-androst-1-ene-3-one;
17f3-(tert-amylcarbonyl)-4-aza-4-5a-androst-1-ene-3-one;
1713-(tert-hexylcarbonyl)-4-aza-4-5a-androst-1-ene-3-one;
1713-(cyclohexylcarbonyl)-4-aza-5a-androst-1-ene-3-one;
1713-(cyclopentylcarbonyl)-4-aza-5a-androst-1-ene-3-one;
1713-(benzylcarbonyl)-4-aza-5a-androst-1-ene-3-one;
1713-(2-pyridylcarbonyl)-4-aza-5a-androst-1-ene-3-one;
1713-(4-pyridylcarbonyl)-4-aza-5a-androst-1-ene-3-one;
1713-(2-pyrrolylcarbonyl)-4-aza-5a-androst-1-ere-3-one;
1713-(2-furylcarbonyl)-4-aza-5a-androst-1-ene-3-one;
1713-(2-thiophenylcarbonyl)-4-aza-5a-androst-1-ene-3-one ;
1713-(2-adamantylcarbonyl)-4-aza-5a-androst-1-ene-3-one;
SUBSTITUTE SHEET

1713-(phenylcarbonyl)-4-aza-5a-androst-1-ene-3-one;
1713-(2-tolylcarbonyl)-4-aza-5a-androst-1-ene-3-one;
1713-(3-tolylcarbonyl)-4-aza-5a-androst-1-ene-3-one;
1713-(4-tolyl~carbonyl)-4-aza-5a-androst-1-ene-3-one;
1713-(2-bromo;phenylcarbonyl)-4-aza-5a-androst-1-ene-3-one;
1713-(2-chlor~~phenylcarbonyl)-4-aza-5a-androst-1-ene-3-one;
1713-(2,6-dicl;~lorophenylcarbonyl)-4-aza-5a-androst-1-ene-3-one;
1713-(2,6-dib:romophenylcarbonyl)-4-aza-5a-androst-1-ene-3-one;
1713-(xylylca:rbonyl)-4-aza-5a-androst-1-ene-3-one;
1713-(phenylei:hyl)carbonyl-4-aza-5a-androst-1-ene-3-one;
1713-(4-dimethylaminophenylcarbonyl)-4-aza-5a-androst-1-en-3-one ;
1713-(3-dimethylaminophenylcarbonyl)-4-aza-5a-androst-1-en-3-one.
1713-(3,4-diet:hylaminophenylcarbonyl)-4-aza-androst-1-en-3-one.
1713-(3,5-dimE~thyl-4-diethylaminophenylcarbonyl)-4-aza-5a-andro;>t-1-en-3-one;
1713-(4-N-methylaminomethylphenylcarbonyl)-4-aza-5a-androst-7.-en-3-one; or 1713-(2-N-eth5~lamino-4-ethylphenylcarbonyl)-4-aza-5a-androst-l.-en-3-one .
1713-(4-phenyl.benzoyl)-4-aza-5a-androst-1-en-3-one;
1713-(3-phenyl.benzoyl)-4-aza-5a-androst-1-en-3-one;
1713-(4-biphenyl)-4-aza-5a-androst-1-en-3-one;
1713-~3-biphenyl)-4-aza-5a-androst-1-en-3-one;
1713-(1-naphthyl)-4-aza-5a-androst-1-en-3-one;
;SUBSTITUTE SHEET

1713-(2-naphthyl)-4-aza-5a-androst-1-en-3-one;
1713-(1-phenanthryl)-4-aza-5a-androst-1-en-3-one;
1713-(2-phenanthryl)-4-aza-5a-androst-1-en-3-one;
1713-(1-biphenyl)-4-aza-5a-androst-1-en-3-one;
1713-(9-anthracyl)-4-aza-5a-androst-1-en-3-one;
17f3-(4-thiophenylcarbonyl)-4-aza-5a-androst-1-en-3-one;
1713-(3-thiophenylcarbonyl)-4-aza-5a-androst-1-en-3-one;
1713-(4-methylthiophenylcarbonyl)-4-aza-5a-androst-1-en-3-one;
1713-(4-methylsulfinylphenylcarbonyl)-4-aza-5a-androst-1-en-3-one;
1713-(4-methylsulfophenylcarbonyl)-4-aza-5a-androst-1-en-3-one;
1713-(3-methylsulfinylphenylcarbonyl)-4-aza-5a-androst-1-en-3-one;
1713-(4-N,N-dimethylaminosulfophenylcarbonyl)-4-aza-5a-androst-1-en-3-one;
1713-(2-ethyl-4-methylthiophenylcarbonyl)-4-aza-5a-androst-1-en-3-one;
1713-(4-thioethylphenylcarbonyl)-4-aza-4-methyl-5a-androst-1-en-3-one;
1713-(4-acetoxymethylthiophenylcarbonyl)-4-aza-4-methyl5a-androst-1-en-3-one;
1713-(2-methyl-4-methylthiophenylcarbonyl)-4-aza-4-methyl-5a-androst-1-en-3-one;
1713-(2-methyl-4-methylsulfinylphenylcarbonyl)-4-aza-4-methyl-5a-androst-1-en-3-one;
173-(2-isopropyl-4-methylsulf ophenylcarbonyl)-4-aza-4-methyl-5a-androst-1-en-3-one;
SUBSTITUTE SHEET

1713-(4-methyl.thiophenylcarbonyl)-4-aza-4-methyl-5a-androstan-3-one;
1713-( 4-methy7.sulf inylphenylcarbonyl )-4-aza-4-methyl-5a-andro.:tan-3-one ;
1713-(4-methyl.sulf ophenylcarbonyl)-4-aza-4-methyl-5a-androstan-3-one;
1713-(4-hydro~yphenyl)-4-aza-5a-androst-1-en-3-one;
1713-(3-hydro~yphenyl)-4-aza-5a-androst-1-en-3-one;
1713-(3,4-dihydroxyphenyl)-4-aza-5a-androst-1-en-3 one;
1713-(3,5-dime~thyl-4-hydroxyphenyl)-4-aza-5a-androst-1-en-3-on~.e ;
1713-(4-hydroxymethylphenyl)-4-aza-5a-androst-1-en-3-one;
1713-(2-hydro$yethylphenylcarbonyl)-4-aza-5a-androst-1-en-3-one;
1713-(4-methoxyphenyl)-4-aza-5a-androst-1-en-3-one;
1713-(4-carboxymethylphenyl)-4-aza-5a-androst-1-en-3-one;
1713-(4-hydroxyphenyl)-4-aza-4-methyl-5a-androst-1-en-3-one;
17f3-(3-hydroxyphenyl)-4-aza-4-methyl-5a-androst-1-en-3-one;
1713-(3,4-dihydroxyphenyl)-4-aza-4-methyl-5a-androst-1-en-3-one;
17f3-(3,5-dimethyl-4-hydroxyphenyl)-4-aza-4-methyl-5a-androst-1-en-3-one;
1713-(4-hydroxymethylphenyl)-4-aza-4-methyl-5a-androst-1-en-3-one;
173-(2-hydroxyethylphenylcarbonyl)-4-aza-4-methyl-5a-~ndrost-1~-en-3-one;
1713-(4-methoxyphenyl)-4-aza-4-methyl-5a-androst-1-en-3-one;
:SUBSTITUTE SHEET

~~~~~1~3 17f3-(4-carboxymethylphenyl)-4-aza-4-methyl-5a-androst-1-en-3-one; and 1713-(4-carboxyphenyl)-4-aza-Sa-androst-1-en-3-one, and the corresponding compounds wherein the 4-hydrogen substituent is replaced in each of the above named compounds by a methyl or an ethyl radical.
The compounds of formula IA of the present invention are prepared by a method starting with the known steroid ester of the formula:
COOCFi3 R" ' R' R' ' N H
R
named 1713-(carbomethoxy)-4-aza-5a-androstan-3-one, which includes the stages of (1) dehydrogenating said starting material to produce the corresponding com-Pound containing a double bond in the 1,2-position of the A-ring, (2) converting the 17-carbomethoxy substi-tuent into a 1713-acyl substituent and, if desired (3) alkylating the A-ring nitrogen to introduce 4-methyl or 4-ethyl substituents into the A-ring. For the dehydeogenation step, it is preferable that the 4-aza nitrogen be unsubstituted, The dehydrogenation step can be carried out, e.g. according to the procedure of Dolling, et al. involving dichlorodicyanobenzo-quinone, JACS (1988) Vol. 110, pp. 3318-3319. Stage SUBSTITUTE SHEET

-(2) may consist of one or more chemical steps and if desired may take place before stage (1) or following stage (1) o:r stage (3).
In accordance with the process of the present invention, the products of our invention are formed by (:L) heating a 1713-alkosycarbonyl-4-aza-5a-androstan-3--one compound III with a dehydrogenating agent such as benzeneseleninic anhydride in refluxing chlorobenzene to form a 1713-alkoaycarbonyl-4-aza-5a-androst-1-en-3-one (IV), (2) the formed 5a-androst-1-en-3-one compound from step (1) is reacted with sodium hydride and under anhydrous conditions in a neutral solvent such as dimethylformamide, (2) contacting t:he resulting reaction mixture with an alkyl (methyl or ethyl) iodide to form the corres-ponding 1713--alkoxycarbonyl-4-alkyl-4-aza-5a-androst-1-en-3-one (V), (3) subsequently hydrolyzing said 1713-alkoxycarbonyl-4-alkyl-4-aza-5a-androst-1-en-3-one with a ,strong base such as aqueous methanolic potassium hydroxide at the reflux temperature, f ol-lowed by acidification and isolation of the resulting steroidal acid, 1713-carboxy-4-alkyl-4-aza-5a-androst-1-en-3-one (;VI), (4) said steroidal acid is then converted tc> its corresponding 2-thiopyridyl ester by refluxing with triphenyl phosphine and 2,2~-dipyridyl disulfide in an inert solvent and the product 1713-(2-pyridylthioc:arbonyl)-4-alkyl-4-aza-5a-androst-1-en-3-one (VII) is' isolated by chromatography on silica, (5) said pyridylthio ester is then reacted with an R2-Li or an R2MgX (g=C1, Br) compound, such as sec-butylmagnesium chloride in tetrahydrofuran, to form SUBSTITUTE SHEET

~~.' ~_''~' the desired product, e.g., 1713-(sec-butylcarbonyl)-4-alkyl-4-aza-Sa-androst-1-en-3-one (VIII) which is isolated by chromatography on silica gel. When the previous reaction is carried out using an R2MgX or, an R2-Li compound in place of sec-butylmagnesium chloride, the corresponding 17J3-(acyl)-4-alkyl-4-aza-5a-androst-1-en-3-one is prepared wherein acyl is R2 carbonyl.
In accordance with the process of our invention, the corresponding 1713-acyl-4-aza-5a-androst-1-en-3-one XV is readily prepared from the 1713(alkoxycarbonyl)-4-aza-5a-androsten-3-one (IV) by repeating the above series of reaction steps but omitting step 2 hereinabove, i.e., treatment of the 4-aza-Sa-androst-1-en-3-one with sodium amide followed by methyl or ethyl iodide.
In accordance with a further alternate process of preparing the compounds of our invention, having only hydrogen as the sole substituent on the ring A-nitrogen, the 1,2-double bond in the A-ring is introduced as the last step of the process. Thus, a 1713-alkoxycarbonyl-4-aza-5a-androstan-3-one (III) is hydrolyzed to the corresponding steroidal acid, 1713-carboxy-4-aza-Sa-androstan-3-one, (IX) which, in turn, is converted to the corresponding thiopyridyl ester, 1713-(2-pyridylthiocarbonyl)-4-aza-5a-androstan-1-one <X) followed by treatment of the ester with an R2MgX or R2Li compound wherein R2 is as defined hereinabove to form a 1713-(acyl)-4-aza-Sa-androstan-3-one (XI) which is dehydrogenated as previously described to produce compound gIV, 1713-(acyl)-4-aza-5a-androst-1-en-3-one.
SUBSTITUTE SHEET

In an additional alternative process for making the compounds of formula I when the starting material is an ester, particularly methyl-ester as shown in formula III-V in the schematic, reaction with a Grignard reagent R2MgX, gives the ketone, 1713-R2C0-, corresponding to the R2 moiety associated with the Grignard reagent.
The 16-methyl derivative wherein R
is methyl are prepared from known 16-methyl-17-l0 acyl-4-methyl-4-aza-Sa-androstan-3-ones, e.g.
4,1613-dimethyl-1713-acetyl-4-aza-5a-androstan-3-one by known dehydrogenation procedures for 4-methyl-4-aza compounds to produce the corresponding 4,16t3-dimethyl-1713-acetyl-4-aza-Sa-androst-1-en-3-one.
The above reactions are schematically represented in the following structural outline:

SUBSTITUTE SHEET

~~04793 COzCH3 COZCH3 COZCH3 R~ R, , , R~ R. . . R~ R. . .
i i V IV III
O I H Ri O I H R. , O I H R. , CHj H H
' COOH ' COOH ' COOH
R, , , Ry. . , R~ R, . .
_ ~
VI XII IX
O I H R. . O I H R , O I H R, .

1 ,° 1 ,° 1 c- X C- X C- X
y, , , R~ R. . , Ry, . .
_ ~
VII XIII X
O I H R, , O I H R. , O I H R. .
2 ~ CH3 H H
1° 1° 1°
~_ R~ ~_ R= ~_ R=
R, R, . . Ry. . , R~ R, , , i i XIII ~ XIV XI
2 5 ° I H R" ° I H R" ° I H R"

X is 2-pycidylthio SUBSTITUTE SHEET

wherein X is a 2-pyridylthio substituent and R2 is defined as he~reinabove.
In the above described reaction Scheme, where R2 is F~-hydroxybiphenyl, this can be derived by starting With an appropriate bromobiphenylylphenol, e.g. p-bromot~iphenylphenol, protecting the phenolic -OH with a conventional blocking group, e.g.
trioganosilyl., i.e. t-butyldimethylsilyl, carrying out the Grign~ard reaction and then deblocking the silyl group by the use of, e.g. refluxing aqueous tetrabutylama~onium fluoride.
Other halo substituted benzenes to form the appropriate Grignard reagent useful in the instant invention will be obvious to one skilled in the art from this disclosure.
By the term "protected hydroxy" as used herein, is meant the alcoholic or carboxylic -OH
groups which can be protected by conventional blocking groups in the art as described in "protective Groups In Organic Synthesis" by Theodora w. Greene, Wiley-Interscience, 1981, New York.
Preferred are the triorganosilyl groups, e.g. t-butyl-dimethylsilyl, phenyldimethylsilyl, diphenylmethyl-silyl, and the like.
By the term "Cl-C4 alkyl" is used herein, is meant linear or branched alkyl, including methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl and t-butyl.
When this reaction scheme is carried out using an R2MgX or R2-Li compound containing an thiophenyl substituted R2, e.g. p-methylthiophenyl SUBSTITUTE SHEET

magnesium chloride, the corresponding 1713-(substituted thio-benzoyl)-4-alkyl-4-aza-5a-androst-1-en-3-one is prepared wherein phenyl is R2.
The Grignard reagent, R2Mgg, f or all the species included Within the scope of this invention, are available or can readily be made by one skilled in the art. For example, where R2 is C1-C4 alkyl thiophenyl, can be formed from the appropriate C1-C4 alkyl thiobromobenzene, e.g. p-methylthiobromobenzene.
The formed Cl-C4 alkyl thiobenzene can be used to further prepare C1-C4 alkyl sulf oxides by oxidation with e.g. m-chloroperbenzoic acid. The resulting sulfoxide can be further oxidized by the use of the m-chloroperbenzoic acid reaction to proceed f or a longer period of time to form the C1-C4 alkyl sulfone .
Further, the sulfoxide can be used in the Pummerer rearrangement to form the corresponding thiol.
The -S02N(C1-C4 alkyl)2 substituted phenyl (R2) is formed from the appropriate bromobenzene, e.g. p-N,N-dimethylaminosulfobromobenzene which is used directly in the Grignard reaction to form the final product.
The thioalkyl groups on the phenyl ring, i.e. -(CH2)mSH, Where m is 1-4, are readily formed via a four step procedure from an alkoxy alkyl phenyl bromide, Br-C6H4-(CH2)m0CH3. Direct addition of the Grignard reagent prepared from above-bromoalkyl phenyl derivative to the thiopyridyl ester results in the lceto derivative, i . e. 17f3(4-methoxyalkyl-benzoyl)-4-aza-5a-androst-1-ene-3-one. This can be SUBSTITUTE SHEET

readily converted into thio analogue via BBr3 at -70°C to form the hydroxyalkyl derivative, followed by displacement by halogen, e.g. bromo and then converting the halogenated compound through NaSH
displacement to give the final mercapto compound.
Where in the Reaction Scheme said pyridylthio ester is reacted with an aminophenyl containing R2-Li or an R2MgX (X=C1, Br) compound, such as p-dimethyl-aminophenyl .magnesium chloride, this is carried out in tetrahydrofuran to form the desired product 17f3-(p-dimethylaminophenyl-carbonyl)-4-alkyl-4-aza-Sa-androst-1-en-3-one (VIII) which is isolated by chromatography on silica gel.
The Grignard reagent, R2MgX, for all of the aminophenyl species included within the scope of this invention, are available and can be made readily by one skilled in the art.
Where in the process said Grignard reagent contains a p:henolic type R2 moiety, then said pyridylthio ester is then reacted with an R2-Li or an R2MgX (X=C1, Br) Grignard reagent, such as p-methoxyphe:nyl-magnesium chloride in tetrahydrofuran to form the ides i red product , a . g . 1713-(p-methoxy-phenylcarbon,yl)-4-alkyl-4-aza-Sa-androst-1-en-3-one (VIII) which is isolated by chromatography on silica gel. When this reaction is carried out using another RZMgX or, an R2-Li compound in place of p-methoxyphe;nylmagnesium chloride, the corresponding 1713-(substituted benzoyl)-4-alkyl-4-aza-5a-androst-1-en-3-one is prepared wherein phenyl is R2.
The Grignard reagent, R2MgX, for all of the species included within the scope of this invention, SUBSTITUTE SHEET

are available and can be made readily by one skilled in the art.
For example, where R2 is hydroxyphenyl, this can be derived by starting with an appropriate bromophenol, e.g. p-bromophenol, protecting the phenolic -OH with a conventional blocking group, e.g.
trioganosilyl, i.e. t-butyldimethylsilyl, carrying out the Grignard reaction and then deblocking the silyl group by the use of, e.g. refluxing aqueous tetrabutylammonium fluoride.
For RZ being hydroxyethylphenyl, the same blocking procedure can be analogously conducted starting with the appropriate hydroxyalkyl bromophenol, e.g. p-hydroxymethylbromobenzene, or p-hydroxyethylbromobenzene.
Where RZ is carboxyphenyl, this can be obtained by the chromic acid oxidation of the appropriate hydroxymethylbenzene, e.g.
p-bromo-hydroxymethylbenzene, formed as described above.
Where R2 is -0-Cl-C4 alkyl, the appropriate bromo-0-C1-C4 alkyl benzene, e.g. p-methoxybromo-benzene, is utilized for the Grignard reaction.
Other halo substituted benzenes to form the appropriate Grignard reagent useful in the instant invention will be obvious to one skilled in the art from this disclosure.
By the term "protected hydroxy" as used herein, is meant the alcoholic or carboxylic -OH
3o groups which can be protected by conventional blocking groups in the art as described in "Protective Groups In Organic Synthesis" by Theodora SUBSTITUTE SHEET

W. Greene, W'iley-Interscience, 1981, New York.
Preferred are the triorganosilyl groups, e.g. t-butyl-dimethylsilyl, phenyldimethylsilyl, diphenylmethylsilyl, and the like.
Also within the scope of the present invention is the use of ketone reduction products of IA, in combination with minoxidil for treatment of patterned alopecia, being secondary alcohols of the formula:

/~~
CH

wherein R is selected from hydrogen, methyl and ethyl;
R2 is (a) a monovalent radical selected from straight or branched chain alkyl, or cycloalkyl, of from 1-12 carbons, which can be substituted by one or more of C1-C2 alkyl or halo;
(b) an aralkyl radical selected from benzyl or phenethyl;
(c) a polycyclic aromatic radical which can be substituted with one or more of:
-OH, protected -OH, -OC1-C4 alkyl, C1-C4 alkyl, halo or nitro;
:SUBSTITUTE SHEET

R

~N'~ f~ ~'~ rr ~ ~J

(d) a monocyclic aromatic radical Which can be substituted with one or more of:
(1) -OH, -OCl-C4 alkyl, C1-C4 alkyl, -(CH2)mOH, -(CH2)n COOH, including protecting hydroxy, where m is 1-4, n is 1-3, providing Cl-C4 alkyl is only present when one of the above oxygen-containing radicals is present;
to (2) -SH, -SCl-C4 alkyl, -SOCl-C4 alkyl, -S02C1-C4 alkyl, -S02N(Cl-C4-alkyl)2, Cl-C4 alkyl -(CH2)mSH, -S-(CH2)n-0_ COCH3, where m is 1-4 n is 1-3, providing Cl-C4 alkyl is only present when one of the above sulfur containing radicals is present;
(3) N(R3)2, which can be protected, where R3 is independently H or Cl-C4 alkyl, where the monoaryl ring can also be further substituted with Cl-C4 alkyl;
and (4) heterocyclic radical selected from 2-or 4-pyridyl, 2-pyrrolyl, 2-furyl or thiophenyl;
R', R " and R "' are hydrogen or 3o methyl, wherein the dotted line represents a double bond which can be present, and pharmaceutically acceptable salts and esters thereof.
SUBSTITUTE SHEET

2'10793 These compounds can be made by conventional sodium borohydride reduction of the carbonyl attached to RZ without reducing the amide carbonyl in Ring A or the 1.2-double bond, if present. If the RZ phenyl contains a carbonyl function, it can be selectively blocked and then regenerated after the borohydride reduction by conventional methods.
They borohydride reduction can be carried out in, e.g. watesr or aqueous methanol, at a temperature of room temperature to 50°C and the product then isolated and purified by conventional means. The compounds are also active as 5-<~lpha reductase inhibitors in the treatment of patterned alopecia.
The. compounds of the present invention, prepared in accordance with the method described above, are, as alre<~dy described, potent agents in combination with an alpha-one adrenergic receptor blocker for the treatment of BPH.

Ir.. this invention, the al-adrenergic receptor blocker, and the 5a-reductase inhibitor are administered in combination separately or as one single combined pharmaceutical composition via parenteral or oral means. Preferably the al-blocker and the 5a-reductase inhibitor are administered orally as separate compositions.
The amount of each component administered is determined by the attending clinicians taking into consideration the etiology and severity of the disease, the patient's condition and age, the potency of each component and other factors.
Tree al-blocker compositions are generally administered in accordance with the current Physician's; Desk Reference (PDR) published by Medical Economics C:o. Inc. of Oradell, NJ 07649. The dosage ranges given here are from the PDR 44 (edition, 1990).
For example, terazosin is administered in a dosage 2o range of about 1 to 10 mg once (q.d.) per day per person whereas prazosin is administered twice (b.i.d.) a day.
The 5a-reductase inhibitor compositions are generally administered in a dosage range of about 5 mg per day per person once each day (q.d.).
In a preferred aspect of this invention, the al-bloc:ker is terazosin which is administered orally to a male human in one daily dose of about 5-10 mg anti the Sa-reductase inhibitor is finaster-ide, which is administered orally in one daily dose of about 5 mg .
A

- _ _ T'he al-blocker and the Sa-reductase inhibitor may be compounded into a single dosage form suitable for oral or parenteral administration.
A tablet or capsule or caplets are particularly convenient. forms for oral administration. Such compositions useful in the present invention are typically formulated with conventional pharmaceu-tical exci.pients, e.g., spray dried lactose and magnesium stearate into tablets or capsules for oral administration. One or more of the active substance:r, with or without additional types of active agents, can be worked into tablets or dragee cores by being mixed with solid, pulverulent carrier substance;>, such as sodium citrate, calcium carbonate or dicalc~'.um phosphate, and binders such as polyvinyl pyrrolidone, gelatin or cellulose derivatives, pos-sibly by adding also lubricants such a magnesium stearate, sodium lauryl sulfate, "Carbowax" or polyethylene glycols. Of course, taste improving substances can be added in the case of oral administration forms .
As further forms of administration, one can use.p:Lug capsules, e.g. hard gelatin, as well as closed softgelatin capsules comprising a softener or plasti~=izer, e.g. glycerine. The plug capsules contain t;he active substance preferably in the form of a granulate, e.g. in mixtures with fillers, such as lactose, saccharose, mannitol, starches such as Potato starch or amylopectin, cellulose derivatives or highly-dispersed silicic acids. In soft gelatin capsules, the active substance is preferably dissolved or suspended in suitable liquids, such as vegetable oils or liquid polyethylene glycols.
A

_ Th.e active ingredient components used in accordance with the present invention may also be formulated into once-a-day or even longer sustained release coff~position by conventional techniques well known in the art.
Ir.~ place of oral administration, the active compounds away be administered parenterally. In such case, one can use a solution of the active substance, l0 e.g., in sesame oil or olive oil.
Following the above treatment using the described regimen, the symptoms of BPH including enlarged prostate volume, nocturia, increased hesitancy, decreased urinary flow, are inhibited, in some cases prevented when treating androgen-dependent diseases such a benign prostatic hypertrophy in accordance with this invention.
To assist in determining. the effect of the prostatic treatment, blood plasma concentrations of testosterone (T), dihydrotestosterone (DHT), and prostate acrid phosphatase (AP) as well as prostate volume are measured. Lowered concentrations of DHT
and prostat:ic AP, a reduction in prostate volume are indicative of successful treatment. The concentra-tions of the above-listed components in plasma can be measured by standard methods well known to those skilled in the art. (See, for ezample, R. Neri and M. Monahan., Invest. Urology (1972), I0, 123-130 for prostatic ESP staining and E. Nieschlay and D. L.
Loriaux, Z. Klin Chem. Klin Biochem (1972), 4, 164 for radioimmunoassay determinations of T.) The prostate volume is measured by rectal examination and/or by transrectal ultrasonography.
A

Objective assessment of the effect of treatment is also measured by physical methods well,known to these skilled in the art of nuclear magnetic reso-nance imaging, as well as by physical examination.
Using a protocol similar to that described above, clinical trials on the effect of the combina-tion of finasteride and terazosin will exhibit an even greater effect on alleviating the symptoms of 1Q BPH in patients which will be greater from either agent alone..
The' method of preparing the compounds of the present invE~ntion, already described above in general terms, may lie further illustrated by the following 15 examples which should not be construed as being limitations on the scope or spirit of the instant invention.

20 Methyl 3-oxy4-aza-5a-androst-1-ere-17J3-carbox~late A ~~uspension of 83.7 g of methyl 3-oxo-4-aza-5a-androstane-17-carboxylate~~ and 126.5 g of benzenes~eleninic anhydride in 2.09 1 of chloro-, benzene was heated at reflex for 2 hours . The reflex 25 condenser w,as switched to a distillation head and the mixture Was distilled slowly to remove water that had formed in t'he reaction (2 hours). The solution was - evaporated to leave 198 g of wet residue. The resi due as a solution in dichloromethane was washed with 3o saturated aqueous NaHC03 solution and saturated NaCl solution, then dried and evaporated to leave 172.4 g.
This material Was chromatographed on 2.56 kg of silica gel eluting first with dichloromethane (5 1) and then A

with 4:I dichloromethane acetone. The desired pro-duct eluted after 8 1 and amounted to 53.4 g. It was rinsed with diethyl ether and dried to leave 49.5 g, of the title compound m.p. 278-280°C. In a similar fashion the following compounds Were converted to their corresponding 1,2-unsaturated derivatives:
O
II
~- ~z II
~ i~H
R
m.p.
la R = CONHC(CH3)3 , 252-254°C
1b - CONHC(CH3)2CH2C(CH3)3 224-226°
Rasmusson Johnston and Arth.
U.S. Pa.tent 4,377,584, March 22, 1983..

Methyl 4-methyl-3-oxo-4-aza-5a-androst-1-ene-17l3-carboxylat.e suspension of 25 g of the product of Example 1 and 2.25 g of sodium hydride in 500 ml of dry dimethylformamide was stirred under nitrogen for 15 minutes. Methyl iodide (15 ml) was added dropZaise and the mixture was stirred f or 30 minutes at room temperature. Additional (5 ml) methyl iodide was added and the mixture was heated at 50°C for A

2 hours. Alter cooling the mixture was diluted with Water t:o a volume of 2 liters. The solid was separated after cooling and amounted to 25.4 g, m.p. 159-16:L°C.
In a similar fashion the following compounds were convert=ed to their corresponding 4-methyl derivatives:
p R
i H ~ i H

m.p.
2a R = CONHC(CH3)2CH2C(CH3)3, 148-150°C
androstane 2b - CONHC(CH3)3; D-1-androstene 153-155°
2c - CONHC(CH3)2CH2C(CH3)3 168-170°
0-1-androstene S-(2-Pyridyl) 4-methyl-3-oxor4-aza-5a-androst-1-ene-17f3-thiocarboxyiatP
A suspension of 25 g of the product of Example 2 in 125 ml of methanol was treated with a solution of KOH (*12.5 g) in 12.5 ml of water . After refluxing for 4 hours, the solution was acidified with 6 NHC1 and then was diluted with water. The crude acid (23.32 g) was separated, dried and had . m.p. 300°C.
The crude, dry acid (23 g), triphenyl-phosphine (36.45 g) and 2,2~-dipyridyldisulfide (30.4 g) were suspended in 138 ml of toluene with stirring for 3 hours at room temperature. The reaction mixture was directly chromatographed on a column of 4.5 kg of silica gel eluting with 9:1 ethyl acetate-acetone to give 20.4 g of the desired product, m.p. 218-220°C.
Continued elution with acetone gave 5.2 g of the methanol addition product, S-(2-pyridyl) la-methoxy-~4-methyl-3-oxo-4-aza-5a-androstane-17t3-thiocarboxylate, m.p. 221-223°C as a by-product.
3A. In a similar fashion the product of Example 1 was converted into S-(2-pyridyl) 3-oxo-4-aza-Sa-androst-1-ene-17f3-thiocarboxylate, m.p. 230-2=12°C.
3F~. In a similar manner methyl 3-oxo-4-aza-Sa-androstane 17-carboxylate was converted into S-(2-pyrid~~l) 3-oxo-4-aza-5a-androstane-1713-thio-carboxylate~, m.p. 232-234°C.
EXp.MPLE 4 N-t-butyl ~+-methyl-3-oxo-4-aza-Sa-androst-1-ene-1713-carboxamide Anhydrous t-butylamine was added to a suspen-sion of 2..'i g of the pyridylthioester of Example 3 in 70 m1 of t~~trahydrofuran. After 60 minutes exposure, the resulting solution was evaporated and the residue was chromai:ographed on 125 g of silica gel. Elution with 20:1 ethy:L acetate dichloromethane afforded 1.5 g of the product, m.p. 152-154°C.
When 1=he example is repeated using an appro priate amine and an appropriate pyridylthioester, the following products were obtained:
4b: N-t-butyl :3-oxo-4-aza-5a-androstane-1713-carboxamide, m.p. 275-276°C.
4c: N-(2,4,4-t:rimethyl-2-pentyl) 4-methyl-3-oxo-4-l0 aza-5a-androst-1-ene-1713-carboxamide, m.p. 168-170°C.

5-Oxc~-3.5-secoetian-3.20-dioic acid To a ;solution of 200 g of 3-oxo-4-etien-1713-oic acid i:n 3.5 1 of ~-butanol at 80° was added a solution of 198.4 g of sodium carbonate in 474 ml of water. A warm (65°C) solution of 948.5 g of sodium metaperiodate .and 6:95 g of permanganate in 3.5 1 of water was added at such a rate that the reaction mixture was maintained at 80°C. After addition the mixture was heated at reflux for one hour. The mixture stood at room temperature overnight. The inorganic salts were removed by filtration and the cake was washed with 225 ml of Water. A solution of 5% aqueous sodium bisulfite was added to reduce the iodine that was present. The ~-butanol was removed under reduced pressure and the aqueous residue was acidified with conc. hydrochloric acid. The separated gum was extracted into dichloromethane and was washed with 5% aqueous sodium bisulfite, saturated sodium chloride solution, then dried and concentrated to an off-white residue (214 g). Crystalline material a was obtained by suspending the residue in ether and diluting with hexane to give 152 g, m.p. 189-192°C.

3-Oxo-4-aza-5-etien-20-oic acid A suspension of 64.7 g of the dioic acid of Step 5 in 3_'~0 ml of ethylene glycol was treated with 80 ml of liquid ammonia. The resulting solution was heated at a rate of 3°/min. up to 180°C and was held at that temperature for 15 minutes. After cooling, 1 liter of crater was added and the mixture was acidified with 10% hydrochloric acid to a pH of 1.5.
The product was removed and washed with water, then air dried to leave 57.5 g of the product, m.p. 310°C.

=~-Oxo-4-aza-5a-etian-20-oic acid A :solution of 136 g of the 5-acid of Example 5B in 16.32 ml of acetic acid was hydrogenated at 60°C in the presence of platinum catalyst (from 16.32 g of Pt02) at 40 psig f or 3 hours. The catalyst was removed and the solution concentrated to give 128.2 g of crude product. The material was washed well with 3 1 of water then filtered an air dried to leave 125 g of the white solid, m.p. 310°.
This material is also obtained by sapon-ification o!: methyl 3-oxo-4-aza-5a-androstane-1713-carboxylate (methyl 3-oxo-4-aza-5a-etien-1713-oate) 3o in 7% methanolic potassium hydroxide followed by an acidic work--up .
A

~~ 0493 - _ N-(2,4,4-tri.methyl-2-pentyl)3-oxo-4-aza-5a-andros-t ane-1713-c a r~oxam i d a A solution of 5.0 g of the product of Example 5C, 3.35 g of dicyclohexylcarbodiimide and 3.18 g of 1-hydroxybenztriazole in 500 ml of dichloromethane was stirred at room temperature overnight. The solid was separated by filtration and the filtrate was treated with 2,4,4-trimethyl-2-pentylamine (t-octylamine). This solution stood at room temperature for 64 hours. A small amount of solid was removed and the solution was washed successively with 10% aqueous sodium hydroxide, water, 10% hydrochloric acid and saturated aqueous sodium chlo::ide. After drying and concentration the crude product was eluted through 240 g of silica gel with 3:7 acetone-dichloromethane to give 5.5 g of the product, m.p. 250-251°C.

Example 5D is repeated using t-butylamine in place of 2,;Z,4-trimethyl-2-pentylamine to obtain N-t-butyl 3-oxo~-4-aza-5a-androstane-1713-carboxamide, m~P. 274-27'5°C.

Synthesis o:f 1713(N-1-adamantyl-carbamoyl)-4-aza-5a-androst-1-en-3-one - 100 mg of the 17-methyl ester (0.305 mmoles) from Example 1 was suspended in 3.0 ml of THF (dried over molecular sieves 3A), and then was added 183.0 mg A

of 1-adaman~~anamine (1.2 mmoles). The suspension was cooled to 5~-10°C and then 590 ~1 of 2.0 M solution, of EtMgBr in THF was added. The resulting mixture was allowed to atir for 10 minutes, and then refluxed for 1-2 hours under N2. The mixture was cooled to 0°C
and then quenched with saturated solution of NH4C1 (about 10 ml.). The organic layer was separated and the aqueous layer extracted with three volumes CH2C12.
The organic layers were combined, washed 2 times with :~20, twice with saturated sodium chloride, and dried over MgS04, filtered and evaporated to dryness in 'vacuum. Crystallization from EtOAc afforded 75.0 mg of product. Recrystallization from MeOH and drying at 110°C f or 2 hours/0.1 mm gave product, mpt. 305-306°C. Molecular weight (by FAB) showed M+=451: Calculated =451.
Anal. Calcd. for C29H42N202~
C,77.28; H,9.40; N,6.21.
Found: C,76.84; H,9.73; N,5.93.

Synthesis of 17~i(N-2-adamantyl-carbamoyl)-4-aza-5a-~ndrost-1-en-3-one Following the above-described general procedure of Example 6 but utilizing 2-adamantamine (prepared by aqueous neutralization of the hydro-chloride and EtOAc extraction and isolation) in place of 1-adamantamine, and carrying out the reflux for 7 hours rather than 1-2 hours, the title compound is prepared , a~.pt . 284-285 °C .

21 0 47 9~3 Synthesis ef 1713(N-1-adamantylcarbamoyl)-4-aza-5a-androstane-3-one 100.0 mg of the adamantyl derivative produced in Example 6 was dissolved in 5.0 ml of dry THF. 300 mg of 57° Pd/C was added and the mixture was hydrogenated for 6.0 hrs. at R.T. at 40 psi.
The mixture was filtered through celite, the cake washed with THF (3 times) and solvent evaporated under vacuum to yield 97.0 mg. of crude above-titled product. NMR showed absence of olefins. The crude material wa.s placed on 15.0 g silica gel column, and eluated with 1:1(CH2C12: acetone). .
Collected fractions afforded a single spot material by TLC weighing 77.98 mg.,NMR was in excellent agreement with the proposed structure.
Recrystalli.zed from EtOAc to yield 65.59 mg of the above-titled product, mp. 323-324°C.
Anal. C;alcd. for C29H4.402N2 1/4 H20:
C,76.18; H,9.81; N,6.13.
Found: C,75.91; H,9.97; N,6.06.

Synthesis of 1713(N-1-adamantylcarbamoyl)-4-methyl-4-aza-5a-androst-1-en-3-one 1;Z0 mg of the thiopyridyl ester of Example 3 was suspended in 20 ml of dry T'HF, to the suspension was added 175.0 mg of 1-adamantanamine under N2. The reaction w,as carried out at R.T. for 16 hours under N2. The reaction was monitored by silica gel TLC, A

using 1:1 acetone: hexane. The product was separated on TLC 20 cm x 20 cm, 1000 Eun silica gel plate, eluted with 1:1 (acetone/hexane).
The product was crystallized from ethyl acetate, to give 50.0 mg of pure material m. pt. 202-205°C.
Molecular Weight (FAB) showed 465; Calc: 465.
Recrystallization afforded 19.14 mg of the above-titled product, m.pt. 202-202.5°C.
Anal. Calcd for C30H44rt2~2~H20:
C,74.64; H,9.60; N,5.80.
Found: C,74.32; H,9.47; N,5.89 Hydrolysis of-Methyl-3-oxo-4-aza-5a-androstane-1713-carboxylate The 17f3-androstane carboxylate starting material of Example 1 was hydrolyzed with 7% KOH
in isopropanol or aqueous methanol, followed by an acidic work-up to give the corresponding 1713 carboxylic acid which was utilized in Example 11.

N-(1-adamantyl)-3-oxo-4-aza-5a-androstane-1713-carboxamide A solution of 5.0 g of the product of Example 10, 3.35 g of dicyclohexylcarbodiimide and 3.18 g of 1-hydroxybenztriazole in 500 mI of dichloromethane was ~ tirred at room temperature overnight. The solid was separated by filtration and the filtrate was treated with 1-adamantamine. This solution stood at room temperature for 64 hours, then filtered, and the solution was washed successively with 10% hydrochloric acid and s~~turated aqueous sodium chloride. After drying with MgS04, it was filtered and concentrated.
The crude ;product was eluted through 240 g of ,silica gel with 3:7 (acetone-dichloromethane) to give 5.5 g of the above-titled product, m.p. 323-324°C.

Synthesis of Benztriazol-1-yl-3-oxo-4-methyl-4-aza-5a-.androstan-1713-carboxYlate A suspension of 83.7 g of methyl-3-oxo-4-methyl-4-aza-5a-androstane-1713-carboxylate. (See Rasmusson, et al. J. Med. Chem 2_~, 2298-2315 ,1986) was hydrolyzed with 7% KOH in aqueous methanol, fol-lowed by an acidic work up to give the corresponding 1713-carboxylic acid.
T'he acid was readily converted into benze-triazvl-1-vl-3-oxo-4 methyl-4-aza-5a-androstane 1713 carboxylate as described in Example 13. The activated ester (the benzotriazoyl derivative) was purified on TLC (4 plates, 20 cm x 20 cm x 20 cm y 1000Eun silica gel) eluted with 4:96 (MeOH-CHC13).
The isolated product was Washed with ether to give the actives ester m.pt. 198-200°C with decomposition.

Synthesis of 1713 (N-1-adamantylcarbamoyl)-4-methyi-4-aza-5a-androstan-3-one :L00.0 mg of the 4-methyl-4-aza-benzotriazole derivativE~ prepared as described in Example 12, was a . dissolved in. 20.0 ml CH2C12. To the clear solution was added 127 mg ef 1-adamantamine. The reaction mixture was stirred overnight at R.T./N2.
Crystallization from EtOAc after filtering the solution through Teflon Acrodisc CR afforded 26.32 mg, m.pt. 210-217°C. The product was further purified on 1.0 g silica gel column (EM silica gel) With 1:1 (acetone-hexane) as eluant to give after l0 recrystallization (ethyl acetate) 21.75 mg of white needles of the above-titled product, m.pt. 203-205°C.
Anal. Calcd. for C~OH46N202~1.5 H20:
C,73.58; H,9.68; N,5.62;
Found: C,73.15; H,9.30; N,5.67. .

Diastereomeric Synthesis of 1713(N-exo-2-norbornanyl-carbamoyl)-4-aza-5a-androst-1-en-3-one) 100.0 mg of the corresponding 4-H thiopyridyl ester of Example 3, prepared by the procedure of Example 3, but utilizing the 4-H methyl ester product of Example 1, (See Rasmusson g~ ~1. J. Med. Chem.
Vol. 29, pp. 2298-2315 (1986), was dissolved in 3.0 ml of dry.THF under N2. To the clear solution was added 477 ~.1 of (~) racemic exo-Z-aminonorbornane.
Allowed the reaction to proceed for 16 hours at R.T./N2. The reaction mixture was evaporated to dryness in vacuum. The residue was dissolved in chloroform. The organic layer was washed with 2.5 N
HC1 acid (3 times); 3 times with water; 3 times with saturated NaCl solution, dried over MgS04, filtered and evaporated to dryness in vacuum to afford 56.3 mg of a racemic diastereomeric mixture.

The crude product was chromatographed on TLC
(2 plates, 20 cm x 20 cm x 500 ~.~m silica gel) eluted with 70:30 (CHCl3:acetone) to yield 43.4 mg.of the above-titled product. Recrystallization from EtOAc yielded 30 mg product, m.pt 245-245.9°C.
NMR (0D013) confirmed the above structure.
FAB mass spectrum calcd. for C26H3802N2~ m/e 411; Found: 411.
Anal. Cal.cd. for C26H3802N2.H20:
0;,72.82; H,9.40; N,6.58.
Found: 0:,73.21; H,9.20; N,6.25.

Synthesis of 1713(N-1-adamantylmethylcarbamoyl)-_4-aza-5a-androst-1-en-3-one 21)0.0 mg of the.4-H thiopyridyl aza steroid, used in Example 14, was suspended in 2.0 ml of dry THF.
T~~ the suspension was added 400 ~.1 of 1-aminomethvlene adamantane via syringe at R.T./N2.
After several minutes, a yellow clear solution resulted and after 1/2 hr., precipitation occurred.
The reaction was allowed to proceed overnight/N2.
Diluted with CH2C12, washed with 10% NaOH, two times, then with H20 two times, followed by 10% HC1 (two times), H20 (two times), and finally two times with satd. NaCl solution.
The organic layer was dried over MgS04, filtered, concentrated in vacuo to obtain the product, as shown by NMR, recrystallized from EtOAc, to yield 149.0 mg product, m.pt 255-257°C with decomposition.
FAB Mass Spectrum, Calcd: m/e 464 f 1 = 465:
Found 465.

Synthesis of 17l3(N-2-adamantylcarbamoyl)-~-aza-5a-androstan-3-one A mixture of 1.09 grams 1713-(N-2-adamantyl-carbamoyl~-4-aza-5a-androst-1-en-3-one (See Example 10 for preparation), 150 m1 of ethanol, and 1.O g. of 3 0 °~°
Pd/C was hydrogenated overnight with shaking under 45 psig. hydrogen pressure. The suspension Was filtered to remove catalyst, and evaporated to dryness to yield a grey residue. This was chromatographed by elution on a 200 ml silica gel column with 40:60 acetone/
methylene chloride eluant to yield 1.0 g of solid, mp. 294-296°C.
Anal. Calcd. for C29H44N202'0.2H20 Calcd. C, 76.33; H, 9.80; N, 6. I4 Found C, 76.23; H, 9.86; N, 5.92 Mass Spec. Analysis by electron impact showed MW of 452.

Synthesis of 17f3-(N-2-adamantylcarbamoyl)-4-aza-4-methyl-5a-androst-1-en-3-one A suspension of 500 mg of 17J3-(N-2-adamantyl-carbamoyl)-4-aza-5a-androst-1-en-3-one, as prepared in Example 16, 10 ml sieve-dried DMF, 140 mg NaH, were heated and stirred at 70°C under a nitrogen atmosphere for 18 hours. Cooled to room temperature and then added 0.4 ml methyl iodide dropwise with stirring which Was continued at 50°C for 3 hours. The reaction mixture was then treated by cooling to room temperature, followed by the addition of 15 ml water.
The mixture was extracted with 3 x 20 ml of CH2C12.
l0 The organic layers were combined, washed with brine, dried and evaporated to yield a white crystalline residue. Recrystallization from ethyl acetate/CH2C12 yielded a pure white solid, mp 246-248°C. .
Analysis calculated for C30H44N202~0.3H20 Calcd. C, 76.65; H, 9.56; N, 5.95 .
Found C, 76.50; H, 9.75; N, 5.84 Mass spectroscopy showed a molecular weight of 464.

Synthesis of 1713-(N-2-adamantylcarbamoyl)-3-oxo-4-methyl-4-aza-5a-androstane 1713-(N-2-adamantylcarbamoyl)-4-methyl-4-aza-androsten-I-en-3-one, (200 mg) as prepared in Example 17, were placed into 25 ml absolute ethanol with 200 mg 30% Pd/C hydrogenation catalyst. The suspension was rocked overnight under 40 psig hydrogen pressure. The suspension was filtered, and the filtrate evaporated to dryness. The residue was recrystallized from hot ethyl acetate to give a white crystalline solid, mp. 113-115°C. Calcd. for C32H5pN203~0.5 EtOAc Calcd: C, 75.25, H, 9.86, N, 5.48 Found C, 75.07; H, 9.52; N, 5.28 Mass spectroscopy depicted a molecular weight of 466 for the non--solvated molecule.

Synthesis ef 17t3-(N-methyl-N-2-adamantyl) carbamo~l-~~-methyl-4-aza-androst-1-en-3-one .
173-(N-2-adamantyl)carbamoyl-4-aza-androst-1-en-3-one (5.0 g) and 1.5 g sodium hydride in 100 ml dry DMF were stirred under dry nitrogen for 3 hours at 40°C. T:he reaction was cooled to room temperature and about 4 ml of methyl iodide was added dropwise and allowed to stir at room temperature for one hour. The reaction was cooled in an ice bath and a large excess of about 250 ml, water was added. The aaueous mixture was extracted with CH2C12 (3 x 100 ml), the organic extracts combined, washed with H20, brine, and then evaporated to dryness to yield crude product. The crude product was eluted on an HPLC
'column (Si gel) with 10/1 acetone/CH2C12 to yield 2 peaks having retention times of 3 CV(B) and 3.8 CV(A).
Peak (A) was analyzed as per the 4-methylaza titled product of Example 15. The second product (B) was analyzed as the 4-methylaza-1713-(N-methyl-N-2-adamantyl/carbamoyl analog, i.e. the titled compound, mp . -163-165 .
Calcd. f or C31H46N202 Calcd. C, 77.77; H, 9.68; N, 5.85 Found C, 77.29; H, 9,79; N, 5.77 Mass spectrometry showed a molecular weight of 478.

Synthesis of 17f3-(N-methyl-N-2-adamantylcarbamoyl) 4-aza-4-methyl-androstan-3-one The crude reaction mixture from Example 19 (4.6 g) was dissolved in 200 ml ethanol and together with 1.0 g 30% Pd/C was hydrogenated under 40-45 Psig a hydrogen atmosphere at room temperature overnight.
The mixture was filtered, residue washed with ethanol.
The ethanol solution was evaporated to dryness to yield a crude mixture. Recrystallized from CH2C12/
diethyl ethe~r/hexane to yield 800 mg of the pure monomethyl ~~ndrostane compound of Example 16, mp 113-115°C. Second and third crops were combined with mother liquor and treated by HPLC as in Example 17 to yield the dimethylated title compound, mp 180-182°C.
Anal. Calcd, for C31H48N202 Calcd. C, 77.45; H, 10.06; N, 5.83 Found C, 77.26; H, 9.87; N, 5.82 Mass spectrometry showed a molecular weight of 480.
A

Methyl 3-ox~~-4-aza-5a-androst-1-ene-1713-carboxylate A suspension of 83.7 g of methyl 3-oxo=
aza-5a-andr~~stane-17-carboxylate~~ and 126.5 g of benzenesele:zinic anhydride in 2.09 1 of chlorobenzene was heated at reflex for 2 hours . The reflex con-denser was switched to a distillation head and the mixture was distilled slowly to remove water that had formed in t'.ae reaction (2 hours). The solution was evaporated t o leave 198 g of wet residue.' The residue as a solution in dichloromethane was washed with saturated a~lveovs NaHC03 solution and saturated NaCl solution, t:~!ien dried and evaporated to leave 172.4 g. This ma~terial~was chromatographed on 2.56 kg of silica gel eluting first with dichloromethane (5 liters) and then with 4:1 dichloromethane-acetone.
The desired product was eluted with 8 liters of the A

2'1 047 93 above-mixed solvent and evaporated to dryness in vacuo to yield 53.4 g solid. It was washed with diethyl ether and dried to leave 49.5 g of the above-titled product, m.p. 278-280°C.
>'~Rasmusson Johnston and Arth. U.S. Patent.4,377,584, March 22, 1983.

S-(2-Pyridyl)-3-oxo-4-aza-5a-androst-1-ene-1713-thio-carboxvlate A suspension of 25.0 g of the above product from Example 1 was saponified with 12.5 g of KOH in 150.0 ml of 5:1 CH30H-H20 under reflux conditions for 4 hours/N2. The mixture Was cooled to 25°C and acidified to pH <2. Water (175 ml) was added gradually with stirring to leave a crystalline precipitate which was collected and washed with water.
After drying, the product amounted to 25 g., m.pt 313-315°C with decomposition.
The crude dry acid (23.0 g) was suspended in 210 ml of toluene, and to the suspension was added triphenylphcsphine (56.0 g) and 2,2'-dipyridyl disulfide (48.3g), and the mixture was stirred at 24°C overnight/N2. The reaction mixture was placed on a column of silica gel (1.3 kg) and Was eluted with 1:1 (acetone/CH2C12). The desired thioester eluted slowly, and after rinsing with ether, yielded 36.8 g of tr.e above-titled product, m.p. 232-235°C.
A

22-Methyl-4-~iza-21-nor-5a-chol-1-ene-3,20-dione To ,3 solution of 7.2 g of S-(2-pyridyl)-3-oxo-4-aza-5a-androst-1-ene-1713-thiocarboxylate in 288 ml of tetrahydrofuran was added .at -78°C 3.3.6 ml of 1.3M S-butylmagnesium chloride. After 30 minutes at -78°C the solution came to room temperature and was treated 'With saturated aqueous NaCl solution.
The product 'was extracted into dichloromethane and was Washed with saturated aqueous NaCl solution and 10% aqueous NaOH solution, then dried and concentrated. The residue was eluted through 430 g of silica gel with 9:1 dichloromethane-acetone to give 4.5 g of the product, m.p. 246-249°C.
When the procedure is repeated using the following reagents, the indicated product is obtained.
Starting Material - Reagent Product S-(2-pyridyl)3- 2-pyrrolyl mag- 1713-(2-pyrrolyl-oxo-4-aza-5o:- nesium chloride carbonyl)-4-aza-androst-1-en.e- 5a-androst-1-ene-1713-thiocarboxylata 3-one m.p. 294-296°C
O
I
H

S-(2-pyridyl)3- sec-butyl mag- 4,22-dimethyl-4-oxo-4-methyl-5a- nesium chloride aza-21-nor-5a-androst-1-ene-17f3- chol-1-ene-3,20-dione thiocarboxylate m.p. 134-136C

S-(2-pyridyl)3- 2-pyrrolyl mag- 4-methyl-1713-(2-oxo-4-methyl-4- nesium chloride pyrrolylcarbonyl)-aza-5a-androst- 4-aza-5a-androst-l0 1-ene-1713-thio- 1-ene-3-one carbox-ylate m.p. 234-238C

S-(2-pyridyl)3- isobutyl mag- 23-methyl-4-aza-oxo-4-aza-5a- nesium chloride 21-nor-Sa-15 androst-ene-17f3- cholane-3,20-thiocarboxylate . dione m.p. 220-222C

20 22-Methyl-4-aza-21-nor-5a-chol-1-ene-3.20-dione alternate route . G _I. H
3 0 ~j A

A solution of 21 g of 22-methyl-4-aza-21-nor-5a-cholane-=~,20-dione and 29.49 g of benzeneseler.~inic anhydride in 552 ml of chlorobenzene was refluxed with water separation for 4 hours. The mixture was concentrated and the residue was redissolved in dichloromethane. After washing with 10% aqueous sodium hydroxide, then 10% hydrochloric acid and saturated aqueous sodium chloride the solution was dried and concentrated to 45 g of yellow residue. This was chromatographed on 1.5 kg of silica gel hacked in dichloromethane and eluted with ethyl acetai:e to give 10.6 g of the product, m.p.
248-251°C.
When the procedure is repeated using 23-methyl-4~-aza-21-nor-5a-cholane-3,20-dione as starting material the product obtained is 23-methyl-4-aza-21-nor-5a-chol-1-ene-3,20-dione, m.p.
283-286°C.
1713-(~hen~~arbonyl)-4-aza-5a-androst-1-ene-3-one To a stirred suspension of 43 g of S-(2-pyridyl)-3-oxo-4-aza-5-alpha-androst-1-ene-17-beta-thiocarboxylate in 500 ml of anhydrous tetra-hydrofuran (THF) was added at -78°C a THF solution of 157 ml of 2N phenylmagnesium chloride over 60 minutes. After stirring at -78°C for 60 minutes, the mixture Was brought to -30°C and was quenched by addition of 10% HC1 while maintaining the temperature below -20°f. After warming to 0°C, the mixture Was diluted with 2000 ml of water and extracted with 4000 ml of dichl.oromethane in portions. The organic layer was washed sequentially with water, 1N sodium hydroxide, water and saturated sodium chloride r solution. Drying with Mg504 and concentration afforded 37.5 g of crude product. Recrystallization from dichloromethane/ ethyl acetate gave the title phenyl ketone (30.4 g, 77% yield).
m. p. 290-29:L°C.
Calc Found N 3.61 3.56 C 77.48 77.16 H 8.26 8.19 17-beta-4-f:Luorophenycarbonyl-4-aza-5-alpha-androst-1-ene-3-one Th~~ procedure of Example 5 Was repeated except using p-fluorophenylmagnesium bromide as the Grignard reagent and the title compound was obtained. m.p. 315-315.5°C:

1713-( r,~ycloh~~ylcarbonvl )-4-aza-5a-androst-1-ene-3-one To a suspension of 34.8 g of the thiopyridyl ester of Example 2 in 700 ml of anhydrous THF was added at -65 degrees C 130 ml of a 2 M ether solution of cyclohexyl magnesium chloride over a period of 20 minutes. A:Eter stirring at -70 degrees C f or 60 minutes the solution was warmed and stirred at -10 degrees C f~~r 60 minutes. The mixture was diluted with 500 ml of dichloromethane and then dropwise With dichloromet:hane, the phases were separated and the organic layer was treated sequentially with water, 1 N sodium hydroxide, water and saturated sodium chloride solution. The organic solution was 2'~ 04793 decolorized with charcoal, filtered and concentrated to a residuE~ which was crystallized from ethyl acetate to give 28.2 of the title compound, m.p.
271.5-277 degrees C.

The title compound of Example 7 was also prepared by the following procedure.
To a mixture of 150 g of methyl 3-oxo-4-aza~-5-alpha-androst-1-ene-17-beta-carboxylate in 2800 ml ~~f anhydrous THF was added with stirring at less than 0 degrees C internal temperature 678 ml of a 2 N ether solution of cyclohexyl magnesium chloride. 'The solution was then refluxed for 6 hours. The cooled (less than l0~degrees C) reaction mixture was acidified with 10%. HC1 solution and was extracted with dichloromethane. The organic layer was washed sequentially with water, saturated NaHC03 solution and saturated NaCl solution. Drying (MgS04) and evaporation left 163 g of crude cyclohexyl ketone. Recrystallization from dichloromethane/
ethylacetate gave 131 g of the pure material.
m.p. 269-270 degrees C.
°/. Calc . Found N 3.61 . 3.61 C 77.37 77.37 H ~ 9.74 10.13 a s 17-beta-(cyc:lopentylcarbonyl)-4-aza-5-alpha-androst-1-ene-3-one When the procedure of Example 7 or 8 was repeated using cyclopentylmagnesium chloride, the title compound was obtained:
m.p. 272-273 degrees C.
Calc Found N 3.66 3.78 C 75.25 74.89 H 9.60 9.54 17-beta-(cyc:lobutylcarbonyl)-4-aza-5-alpha-androst-1-ene-3-one When the procedure of Example 7 or 8 was repeated using cyclobutylmagnesium chloride, the title compound was obtained:
m.p. 288-289 degrees C.

7.Calc Found N 3.94 3.87 C 77.71 78.06 H 9.36 9.61 Synthesis of 17-13-(4-Phenylbenzoyl)-4-aza-5a-androst-1-en-3-one To a suspension of 258.0 mg of dry activated magnesium chips in 5.0 ml of dry THF was added 932.0 A

mg of 4-bromobiphenyl in 5.0 ml of dry THF under N2.
The reactior.~ was run in an ultrasonic bath at a temperature range of 24-30°C. To the well-agitated mixture was added dropwise 30 ml of 1,2-dibromoethane/
N2. The reaction was allowed to proceed for 1-1 1/2 hours at 28°C/N2. The concentration of the Grignard reagent was 4.0 mmoles in 10.0 ml of dry THF.
The' steroid from Example 2 (205.0 mg, 0.5mmo1 of t:hiopyridyl ester) Was suspended in 2.0 ml of dry THF,~cooled to -80°C and the above Grignard 3.80 ml was added via syringe to the steroidal suspension over 5-10 minutes/N2. The reaction was allowed to proceed for 1 hour at -80°C/N2 and then at -10°C for an additional hovr/N2. The solution was diluted with 10.0 m1 of methylene chloride and quenched wii:h saturated aqueous solution of NH4C1 to pH=4. The organic layers were separated, washed 3 times with ~.~ater, 3 times with saturated sodium chloride, dried over MgS04, filtered, and evaporated under vacuum to afford 156.2 mg of crude product.
Crystallization from EtOAc gave the above-titled product in '98.58 mg, m.pt. 290°C-290.5°C.
Anald . ~~alcd . for C31H35N02 C,82.08; H,7.78; N,3.09;
Found: C,81.84; H,8.01; N,3.06.
FAB: Calc. for C31H35N~2~ 453; Found: 453.

17-~-~3-Phe~~hPn~ovl)-4-aza-5a-androst-1-en-3-one To a suspension of 258.0 mg of dry activated ma~_nesium chips in 8.0 ml of dry THF Was added 932.0 mg of 3-bromobiphenyl in 2.0 ml of dry THF under N2.
A

~~ 047 93 The reaction was run in an ultrasonic bath at a temperature range of 24-30C. To the well-agitated _ mixture was added dropwise 30 microliters of 1,2-dibromoethane/N2. The concentration of the Grignard reagent was 4 mmoles in 10.0 ml of dry THF.

The steroid from Example 2, 205.0 mg (0.5 mmoles) was suspended in 2.0 ml of dry THF, cooled to -80C and th.e above prepared Grignard, 3.80 ml, was l0 added via syringe to the steroidal suspension over 5-10 minutes/N2. The reaction was allowed to proceed for 1 hour a.t -80C/N2 and then at -10C f or an additional hour/N2. The solution was_diluted with 10.0 ml of methylene chloride and quenched with a saturated aa~ueous solution of NH4C1 to pH=4. The organic layers were separated, washed 3 times with water, 3 times with saturated sodium chloride, dried over MgS04, filtered, and evaporated under vacuum.

Crystallization from ethyl acetate afforded 122.84 mg of product. The material was purified on 20.0 g of silica gel column using 70:30 (CHC13-acetone) as eluant, to ~;ive a single spot material 117.0 mg of the above-titled compound, m.pt. 184-185C.

Anald. Calcd. for C31H35N02:

' C,82.08; H,7.78; N,3.09;

Found: C,82.28; H,8.04; N,2.98.

FAB: Ca:Lcd. for C31H35N02: 453; Found: 453.

Synthesis o:: 17-!3-(4-Methylthiobenzoyl)-4-aza-5-a-a:zdrost-1-en-3-one To a suspension of 250.0 mg of dry activated A

magnesium chips in 8.0 ml of dry THF was added 812.0 mg of p-bromophenyl methyl sulfide in 3.0 ml of dry THF under N2. The reaction Was run in an ultra-s sonic bath at a temperature range of 24-30°C. To the well-agitated mixture was added dropwise 40 ~.l.of 1,2-dibromoethane/N2. The reaction was allowed to proceed f or 1 to 1 1/2 hours at 28°C/N2. The concentration of the Grignard reagent was 4.0 mmoles in 10 ml of dry THF.
The steroid from Example 2, i.e. the pyridylthio ester, 205 mg, was suspended in 2.0 ml cf drv THF, cooled to -80°C and the above prepared Grignard was added via syringe to the steroidal suspension in 5-10 minutes/N2. The reaction was allowed to proceed for 1 hour at -80°C/N2 and then at -10°C f or an additional hour/N2. The solution was diluted with 10.0 ml of methylene chloride, and quenched with saturated aqueous solution of NH4C1 to pH=4. The organic layers were separated, washed 3 times with water; 3 times with saturated sodium chloride, dried over MgS04, filtered, and. evaporated under vacuum to afford 105.0 mg of crude product.
The crude product was chromatographed on TLC
(one plate, 20 cm x 20 cm x 20 cm x 1000 ~m silica gel) eluted with 80:20 (CH2C12-acetone) to afford 66.0 mg of single spot material. Crystallization from EtOAc afforded 45.0 mg of the above-titled compound, m.pt. 286-287°C.
FAB for C26H33N02S (Calcd.) 424; Found 424.

Synthesis of 17-J3-(4-methylsulfinylbenzoyl) and -(4-methvlsulfonvlbenzovl)-4-aza-5a-androst-1-en-3-one A. Oxidati~
19.91 mg of the methylthio product from Example 13 was dissolved in 2.5 ml of CH2C12, cooled to 0-(-2)°C and was treated with a solution 9.6 mg of m-chloroperbenzoic acid in 1.0 ml of CH2C12 over a period of 4 minutes. After stirring for 1 hour at 0-(-2)°C, the reaction was diluted with 10 ml.
CH2C12. The layers were washed subsequently with 2.5% NaHC03, H20 and saturated NaCl solutions. The organic layer was dried over MgS04 overnight, filtered anal evaporated in vacuo to yield 17 mg product. Crystallization from EtOAc gave 11..8 mg 'of the above-titled compound, a solid, mp. 313-313.5°C
(with dec.).
Anal. C:alcd. for C26H33N03S ~ 1/4H20:
C,70.31; H,7.60; N,3.15;
Found: C,70.47; H,7.70; N,3.00.
FAB for C26H33N03S (Calcd. 440); Found 440.
Sulfone Fifteen percent (157°) of the corresponding sulfone, li'J3-(4-methylsulfonyl benzoyl) derivative, was isolatE~d by chromatography from the reaction as a byproduct. Recrystallized from EtOAc to yield a solid, mp. 279-279.5°C. Molecular weight by FAB
showed 456; calculated 456.
Anal. i:or C26H33N04S ' 0.25 H20 Calc: C,67.87; H,7.28; N,3.04.
Found: C,67.96; H,6.72; N,2.95.
A

-~o-Synthesis o:E 17-!3-(4-acetoxymethylthiobenzoyl)-4-aza-5a-andr~~st-1-en-3-one Trifluoroacetic anhydride (165 ~1) was dissolved i:a 780 ~.1 of acetic anhydride and kept for 5 hours at room temperature (RT).
To 300 ~,1 of the above solution of mixed anhydrides was added 34.15 mg pure self oxide from Example 14 'with stirring. A few minutes later 54.0 ~1 of 2,6-lutidine was added and the reaction was allowed to stir at RT/N2 for 17 hours.
The liquid anhydrides were removed under reduced pressure and the remaining residue extracted (4 times with CHC13). The CHC13 extracts were washed subsequently with dilute HC1; 5°/. NaHC03 solution, 3 times; 3 times with H20; and finally with saturated NaCl solution, and then dried over MgS04 filtered and evaporated the solution to dryness ~ vacvo to yield 42.1 mg of crude product.
The crude product from Step A was purified by chromatography on silica gel using 95:5 (CHC13-acetone) as eluant- and then crystallizing the obtained solid from EtOAc to yield 17.8 mg of the above-titled compound as crystals, m.pt. 235-236°C
(dec.).
Anal. Calcd. for C2gH3504NS - 1/4 H20:
C,68.57; H,7.40; N,2.86;
Found: C,69.02; H,7.39; N,2.73.
F~ f or C28H2g04NS calcd.: 482; Found 482.
The NMF: (proton) was in agreement with the assigned product structure.
a Synthesis of 17l3(4-mercaptobenzoyl)-4-aza-5a-androst-1-en-3 one 40.0 mg of the acetoxy-methyl-thio derivative from Example 15 Was suspended in 3.0 ml of isogropanol. The reaction mixture was flushed several times with N2, and with vacuum, and the system kept under nitrogen atmosphere. To the above mixture was added 40.0 mg of k2C03 in 2.00 ml of water (free of oxygen) via syringe, and the temperature of the reaction mixture Was allowed to rise to 80°C under gentle reflux under slight vacuum for 10 minutes, and then under N2 for 1 hour. After 1 hour, the reaction mixture was a.clear yellow solution. It was brought to R.T., cooled to~0-5°C
and quenched with 2.5 N HC1 acid/N2. The reaction mixture was extracted 4 times with CH2C12. The organic layer was washed with H20 4 times; 3 times with satu rated salt solution, and finally dried over Mg504. Filtered and evaporated to dryness in vacuo to yield 36.9 mg of crude product. The crude product was dissolved in 2.0 ml of CHC13, filtered through Teflon (Acrodisc CR) and purified by preparative HPLC
on silica ;,e1 and eluted with 60:40 (CH2C12-acetone). Crystallization, from EtOAc afforded a single spot material, 20.7 mg of the above-titled compound, m.pt. 285-286°C.
Anal. Calcd. for C25H3102NS . 1/2 H20:
C,72.19; H,7.69; N,3.24;
Found: C,71.82; H,7.43; N,3.26.
FAB: Calcd. for C25H3102NS: 410; Found: 410.
A

2~ 0793 - 72 _ Synthesis of 17-!3-(4-Dimethylaminobenzoyl)-4-aza-5-a-androst-1-er.;-3-one To a suspension of 291.0 mg of dry activated magnesium chips in 8.0 ml of dry THF was added 800.0 mg of 4-bromo-N,N-dimethylaniline in 2.0 ml of dry THF under N~,. The reaction was run in an ultrasonic bath at a temperature range of 24-30°C. To the well-agitated mixture was added dropwise 30 ml of 1,2-dibromoethane/N2. The reaction was allowed to proceed for 1 to 1 1/2 hours at 28°C/N2. The concentratic>n of the Grignard reagent was 4.0 mmoles' in 10.0 ml of dry THF.
The' steroid from Example 2 (205 mg of , pyridyl thioester) was suspended in 2.0 ml of dry THF, cooled to -80°C and the above Grignard 3.8 ml (3 equivalents) was added via syringe to the steroidal suspension over 5-10 minutes/N2. The reaction was allowed to proceed fo a l hour at -80°C/N2 and then at -10°C for an additional hour/N2. The solution was diluted with 10.0 ml of methylene chloride and quenched with a saturated aqueous solution of NH4C1 to pH=4. The organic layers were separated, washed 3 times With cJater 3 times with saturated sodium chloride, dried over MgS04, filtered, and evaporated under vacuum to afford 151.3 mg of crude product.
Crystallizai:ion from ethyl acetate gave 124.5 mg of the above-titled compound, m.pt. 268.5-269°C.
F~ : C<~lcd . C27H36N202 v 421; Found : 421.
The NMR (proton in CDC13) confirmed the assigned structure.
A

General Procedure for Preparing Protected Silyl , perivatives 1.f mole of phenol or its derivatives, or 1 mole of alcohol is treated with 1.5 liters of dry methylene cr;loride. To the clear solution is added dry 3.0 moles of imidazole/N2. The clear solution is cooled to 0°C/N2, and 2.0 moles of t-butyl dimethyl chlorosilane in 300.0 ml of dry methylene chloride is added dropwise at 0°C/N2. Towards the end of the addition, precipitation occurs. The ice bath is removed, ane. the reaction is allowed to proceed overnight at: R.T./N2. Filter, wash the cake with cold CH2C12 solution, and the solvent is evaporated in vacuo to afford crude product. The crude product was readily purified by filtering through a silica gel column. (1 gr. of crude product per 100 g of silica gel, using CH2C12 as eluant) This method gives about 99% of pure silyl derivatives of phenols and alcohol; .

Synthesis of' 17-t3-(4-Hydroxybenzoyl)-4-aza-5-a-androst-1-ene-3-one A. Grignarcf Reaction To a suspension of 1.22 g of dry activated magnesium chips in 20.0 ml of dry THF was added 5.6 g of 1-bromo-~~-(tertiary-butyl dimethyl silyloxy)benzene (Prepared from p-bromophenol by the General Procedure detailed above) in 10.0 ml of THF under N2. The reaction was run in an ultrasonic bath at a tem-perature range of 24-30°C. To the well-agitated mixture was added dropwise 150 ~1-200 ~.1 of 1,~-dibromoe~thane/N2. The reaction was allowed to proceed for 1-1 1/2 hours at 28°C/N2. The concen-tration of t:he Grignard reagent formed was 19.5 mmoles in 3().0 ml of dry THF.
The steroid from Example 2 (1.02 g, 2..49 mmoles) was suspended in 20.0 ml of dry THF, cooled to -80°C and the above-prepared Grignard (11.5 ml) l0 was added vi.a syringe to the steroidal suspension in 5-10 minute:>/N2. The reaction was allowed to proceed fer 1 hour at -80°C/N2, and then at -10°C for an additional hour/N2. The reaction solution was diluted with 10.0 ml of methylene chloride and 15 quenched wii_h a saturated aqueous solution of NH4C1 to pH=4. O::ganic layers were separated, washed 3 times with 1320, 3 times with saturated sodium chloride, dried over MgS04, filtered, and evaporated under a vacuum to a yellow color solid.
20 Crystallization from ethyl acetate afforded 607 mg of product m.p. 248-249°C.
Anal. C~alcd. for C31H4503NSi:
~~,73.32; H,8.93; N,2.75 Found: ~~,73.27; H,8.99; N,2.75.
25 FAB: Found 508; Calc. 508. ' B. Desilvl i n Dissolved 1.3g of product from above step A
in 20.0 ml of dry THF. Cooled to -5°C and added 437 30 ~1 of glacial acetic acidlN2. To the cold solution at -5°C was added via syringe 3.0 ml tetra-n-butyl-ammonium fluoride dropwise under N2 atmosphere.

-~5-Allowed the reaction to proceed under stirring for 1 1/2-2 hours at 0° to -5°C/N2. The reaction mixture was poured into a 2-layer mixture of ethyl acetate/sod.ium bicarbonate saturated solution at 0°C. The cater layer was separated and further extracted with EtOAc 3 times and with CH2C12 (3 times).
The organic layers were combined, washed 3 times with H20, 1 time with saturated sodium chloride solution, and dried over MgS04, filtered and evaporated to dryness under vacuum. The crude product way; crystallized from ethyl acetate to afford 977.9 mg, and further recrystallized from methanol to afford 842.3 mg of the above-titled product, m.pt.
296-297°C.
Anal. Calcd. for C25H31N03~1/3 H20.:
C,75.15; H,7.98; N,3.51.
Found: C,75.13; H,7.76; N,3.54.
(Mass :>pec.) FAB: Found 394; Calcd. 394.

17-f3-(3,5-dimethyl-4-hydroxybenzoyl)-4-aza-5a-androst-1-c~ne-3-one A. Preparation of Grignard Reagent To a suspension of 260.0 mg of dry activated magnesium ~~hips in 6.0 ml of dry THF was added 628.0 mg of 1-br~~mo-3,5-dimethyl-4-tertiary-butyl-dimethyl-silyloxybe:nzene (prepared from 4-bromo-2,6-dimethylphenol by the General Procedure described above) in 4.0 ml of THF/N2. The reaction was conducted in an ultrasonic bath at a temperature 2'104793 range of 24~~-30°C. To the well-agitated mixture was added dropwise 40 ~.1 of 1,2-dibromoethane/N2. The reaction was allowed to proceed for 2 hours/N2.
The concentration of the Grignard reagent thus formed was 2 mmoles in 10.0 ml of dry THF.
ThES steroid from Example 2 (205.0 mg (0.5 mmoles) was suspended in 3.0 ml of dry THF, cooled to -80°C, and '~.5 ml (1.50 millieq. ) of the above-prepared Grignard Was introduced via syringe to the steroidal suspension over a period of 5-10 minutes/N2. The reaction was allowed to proceed for 1 hour at -!30°C/N2 and then at -10°C f or additional hour/N2.
Th!° reaction was quenched with 1N HC1, and then diluted with chloroform. The organic layers were combined, washed 3 times with H20, 3 times with saturated sodium chloride and dried over MgS04, filtered and concentrated in vacuo. The crude residue was washed with ether to afford 121.7 mg of product.
The=_ crude product was dissolved in 70:30 (CHC13-acetone), filtered through Teflon (Acrodisc CR) and purified by preparative HPLC (Waters Prep-pak) on silica g~~l and eluted with 70:30 (CHC13-acetone).
The major component was recrystallized from ethyl acet ate to give 52.0 mg of product m.pt 245-245.5°C. .
Anal . C,alcd . for C33H4903NSi ~~,~3.96; H,9.23; N,2.61 found: ~~,74.06; H,9.33: N,2.64 (Mass Svpec.) FAB: Found: 536; Calc.: 536 A

-. B. Debloclcing the Silvl Derivative Dissolved 54.0 mg of the above product from A in drv THF (1.3 ml). The clear solution was cooled to 0°C, anti 29 ~1 of glacial HOAc was added via syringe/N2. To the above solution was added drop-wise 172 ~.:L of tetra-n-butylammonium fluoride at 0°C
dropwise via syringe/N2. Allowed the reaction to proceed at 0°C/N2 for 1 1/2 hours. The reaction l0 mixture was poured into ice/saturated NaHC03 solu-tion and EtOAc. Stirred for several minutes. Allow the layers to separate, and the H20 layer was extracted 3 times with EtOAc and 3 times with.CHCl3.
C~~mbined the organic layers and washed 3 times with H20, then 3 times with saturated NaCl, and then dried over MgS04, filtered and evaporated to dryness in vacuum to afford 52.2 mg.
T:he product Was crystallized from EtOAc to give 22.5 mg of the above-titled product m.pt 305-306°C.
Calc. for C27H3503N~H20:
C, 73.77; H, 8.49; N, 3.10.
Found: C, 73.62; H, 7.90; N, 3.44.
(Mass Spec.) FAB: Calc:422; Found: 422 Synthesis of 17-13-(4-Methoxybenzoyl)-4-aza-5-a-androst-1-~ne-3-one A~ ri n rd Reaction - To a suspension of 258.0 mg of dry activated Mg chips in 8.0 ml of THF/N2 was added 748.0 mg p-bromoanisole in 2.0 ml of dry THF. The reaction A

_~8_ was run in an ultrasonic bath at a temperature range of 24-30°CIN2. To the well-agitated mixture was added dropmise 30.0 ~1 of 1,2-dibromoethane as a catalyst. The reaction was allowed to progress for 1-2 hours .at 28°C. The formed Grignard reagent had a concentration of 4 mmoles in 10.0 ~1 of dry THF.
The steroid from Example 2 (205.0 mg (0.50 mml) was suspended in 2.0 ml of THF, cooled to -78°C
and the above-prepared Grignard reagent (3.75 ml; 1~
milliequivalents) was added via syringe to the steroidal suspension over 5-10 minutes/N2 and then at -10°C for an additional hour/N2. The resulting reaction mixture was a clear solution, which was cooled to 0-5°C, diluted with chloroform and quenched with 1N HC1 acid. The organic layers were separated, Washed With H20 2 times, followed with saturated NaCl solution, dried over MgS04, filtered and evaporated in vacuo. The crude product was washed with ether, and crystallized from EtOAc to give 110 mg of product a~.pt 305-306°C.
Further purification was carried out by chromatographic isolation on a TLC. plate, (20 cm x 20 cm x 1000 Etm), using as eluant, 70:30 <CHC13:
acetone). Recrystallization from EtOAc yielded 78.56 mg of the above-titled product, m.pt 305-306°C (dec.).
(Mass Spec) FAB: Calcd.,408; Found 408.

Synthesis of 17-f3-(3-hydroxybenzoyl)-4-aza-5a-andLOSt-1--ere-3 one A. Prepa::ation of Grignard Reaeent '.Co a suspension of 230.0 mg of dry activated Mg chips in 2.0 ml of dry THF was added 722.4 mg of _ 79 _ 1-bromo-3-t:ertiary-butyl dimethyl-silyloxybenzene (prepared from 3-bromophenol by the General Procedure described above) in 8.0 ml of dry THF/N2. The reaction was run in an ultrasonic bath at a temper-ature range' of 24-30°C/N2. To the well-agitated mixture wa:; added dropwise 20. 0 ~1 of 1, 2-dibromoethane/N2. Allowed the reaction to progress for 2 1/2 tours at 28°C/N2. The formed Grignard reagent had a concentration of 2.52 mmoles in 10.0 ml of dry THF.
Tree steroid from Example 2 (205.0 mg (0.5 mmoles) wa:; suspended in 2.0 ml of TfiF, cooled to -78°C and t:he above-prepared Grignard reagent (6.0 ml, (1.5 mi.lliequivalents) was added via syringe to the steroidal suspension over 5-10 minutes/N2, and then stirred for an additional hour at -10°C/N2. The clear reaction mixture was quenched at 0 to -5°C with 1N HC1 acid for 10.0 minutes and diluted with CHC13.
The combined organic layers were washed 3 times with H20, 3 times with saturated NaCl, and then dried over MgS04, filtered and concentrated in vacuo to afford crude product. The product was purified on silica gel column and was eluted with 70:30 (CHC13-acetone): The desired product amounted to 58.0 mg, as the si15~1 derivative, 1713-(3-tertiary-butyl-dimethylsil.yloxybenzoyl)-4-methyl-4-aza-5a-androst-1-en-3-one.
W ~~1ng 5i.6 mg of the above silyl derivative was dissolved i.n 3.0 ml of dry THF. The solution was cooled to 0°C, and 20 ~.1 of glacial acetic acid was a -$o_ introduced via syringe. To the clear solution was added 130.0 N.1 of (n-butyl)4NF via syringe, and allowed the reaction to proceed for 1 hour/N2 at 0°C. The re2.ction mixture was poured into EtOAc/NaHC03 sat. solution @ 0°C. The water layer was separated, extracted 3 times with EtOAc and then 3 times with chloroform. The organic layers were combined and washed 3 times with H20, 3 times with l0 saturated NaCl solution, dried over MgS04, filtered and evaporatE~d in vacuo to give 57.11 mg of crude product. The' crude product was chromatographed by TLC (one plai:e, 20 cm x 20 cm x 250 ~.m silica gel), eluted with '10:30 (CHC13-acetone) to afford 44.5 mg 15 of the above-titled product. Recrystallization from EtOAc gave 2'3.30 mg m.pt 279-280°C.
Anal. Calcl. for C25H31N03~ 8H20:
C,73.60; H,8.06; N,3.43.
Found: C,73.26; H,8.22; N,3.28.
20 (Mass Spec.) FAB: Calcd: 394; Found 394.

Synthesis ef 17-J3-(4-hydroxymethyl-benzoyl)-4-aza-5a-androst-1-en-3-one A. Preuaration of Gri,~nard solution To a suspension of 100.0 mg (4 mmoles) of dry activated Mg chips in 5.0 ml of dry THF/N2, was added 753.0 mg (2.5 mmoles) of 1-bromo-4-3o tertiary-butyl dimethyl silyloxy methyl benzene (prepared from 4-bromobenzyl alcohol by the General Procedure described above). The reaction was con-ducted in an ultrasonic bath at a temperature range of 24-30°C/Pz2. To the well-agitated mixture was a added 20 ~1 of 1,2-dibromoethane/N2. Allowed the reaction to progress for 2 hours at 28°C/N2. The concentration of formed Grignard was 2.5 mmoles in . 0 ml of d ry THF .
B. GriEnard Reaction The steroid from Example 2 (205.0 mg (0.5 mmoles) was suspended in 2.0 ml of THF, cooled to -78°C, and the above-prepared Grignard (3.0 ml, 3.75 millieauivalents) was introduced via syringe into the steroidal suspension over 5-10 minutes/N2. Allowed the reaction. to progress for 1 hour at -80°C/N2, and ' then for an additional hour at -10°C/N2. The clear reaction solution was quenched with saturated NH4C1, at 0° to -5°C, and then diluted with CH2C12. The organic layers were separated and washed 3 times with water, 3 tines with saturated NaCl, dried over_MgS04, filtered anc', evaporated in vacuo to dryness. Crude product was crystallized from EtOAc to give 137.8 mg of silyl product.
(Mass Spec.) FAB: Calcd for C30H4103NSi: 521.75 Found : _'~22 . 0 .
C~ Deblocki~g of Silvl Derivative The' product from Step B above (Z3.67 mg) was dissolved in 0.5 ml of THF and 0.5 ml of MeOH and cooled to.0°C/N2. To the cold solution was added 10 ~.1 of concentrated sulfuric acid (987°) . The reaction was stirred for 45 minutes at 0°C/N2. To the cold solution at 0°C was slowly added a saturated solution of NaHC03 acid chloroform. Extracted 3 times with CHC13. The organic layers were washed 3 times with water, 3 times with saturated NaCI, solution dried over MgS04, filtered and evaporated to dryness in vacuo, to afford 10.18 mg. After chromatography on a TLC plate (elution with 1:1 CHC12: acetone) The crude product was crystallized from EtOAc to give 6.0 mg of the above-titled product, m.pt 318-320°C.
Anal. Calcd. for C26H3303N~1/3H20:
C,75.41: H,7.94; N,3.38.
'Found: C,75.61; H,7.84; N,3.12.
(Mass Spec.) FAB: Calc.: 408; Found: 408 Synthesis of 17-13-(4-Carboxybenzoyl)-4-aza-5a-androst-1-en-3-one A. Oxidati~
90.2 mg of the product from Example 23 was dissolved in 2.63 ml of glacial acetic acid and to the clear solution was added 69.0 mg of Cr03 (previously dried over P205 at R.T. for 2 days in vacuo). After stirring overnight, the reaction mixture was diluted with water and allowed to age overnight in the refrigerator. The reaction mixture was filtered and the mother liquor and washes were extracted overnight using a liquid-liquid-extractor, (Fi20-EtOAc) under reflux conditions. The organic layer was cried over MgS04, filtered and evaporated in vacuo. The residue was dissolved in hot MeOH, filtered and evaporated in vacuo to afford a product weighing 32.0 mg.
FAB: Calc. for C26H3104N~ 422.0;
Found: 422.
a B. Purifir,~~tion The above free acid was purified by dissolving 'the above product in 1N sodium hydroxide solution. 'the clear solution was extracted 3 times with EtOAc. The aqueous basic solution was cooled and acidified with 1N HC1 acid dropwise to pH=4 with stirring. 'the reaction mixture Was allowed to age for 1 hour at 0°C. It was filtered and the residue was washed with cold water. Dried overnight to 100°C
in vacuum <~3.2 mm pressure.
Yield o:E the above-titled free acid was 9.85 mg.
FAB: ~a.lc. for C25H3104N~ 422; Found 422.
NMR analysis indicated the product to be an acid.
C. Sodium Salt of Above Acid 4.9 mg of the above product acid B_was dissolved i:n 2.0 ml of hot methanol. To the clear solution, was added 11.6 ~.1 of 1N NaOH(aq). To 2p solution after methanol evaporation in vacuo, was added water to reach pH 7.21. The aqueous solution was freeze dried to give 6.3 mg of the sodium salt ef the above-titled product.

Synthesis of 17-J3-(4-hydroxyethylbenzoyl)-4-aza-5a-androst-1-en-3-one A. ri nard Reagent 3o To a suspension of 252 mg of dry activated Mg chips in 10.0 ml of dry THF Was added 1.26 g (4 mmoles) of 1-bromo-4 tertiary-butyl dimethyl silyloxy ethyl benzene (prepared from 2-(p-bromophenyl) ethanol a - 84 - _ by the General Procedure described above). The reaction mixture was vigorously stirred using an ultrasonic vibrator/N2. To the well-agitated mixture was added 40 ~.1 of 1,2-dibromoethane to catalyze the above reaction. Allowed the reaction to progress for 3 1/2-4 hovrs/N2. The concentration of formed Grignard reagent Was 4 mmoles in 10 ml of THF.
B~ ri n rd Reaction 2(?5.0 mg (0.5 mmoles) of the aza-steroid of Example 2 c~~as suspended in 2.0 ml of dry THF/N2, cooled to -~80°C, and the above-prepared Grignard (3.75 ml, 1..5 milliequivalents) via syringe was introduced into the steroidal suspension over 5-10.
minutes/N2. The reaction was run at -80°C fo-r 1 hour/N2 anc! then for an additional hour at -10°C.
The reaction was quenched with a saturated solution of NH4C1 at: 0-5°C and diluted with 10.0 ml of CH2C12. The organic layers were washed with water (3 times), saturated NaCl solution (3 times), dried with Mg504, filtered and evaporated in vacuo to dryness.
The crude product was crystallized from EtOAc overnight t:o give 152.0 mg of product m.pt. 233-234°C.
Anal. Calcd. for C33H4903NSi:1/4 H20:
C,73.55; H,9.18, N.2.59.
Found: C,73.45; H.8.94; N,3.21 FAB: Calc. 536; Found: 536 C~ Desilv:Lation 70.8 mg of product from Step B, was dissolved :in 1.45 ml of methanol and 1.45 ml of THF.
The solution Was cooled to 0-5°C and 29 ~1 of conc.
A

H2S04 was added via syringe under N2. The reaction was allowed to proceed for 45 minutes/N2. The reaction was carefully quenched at 0°C with a saturated solution of NaHC03, and extracted 3 times with CH2C12. The organic layers were separated, washed with water (3 times), then With saturated NaCl solution, dried over MgS04, filtered and evaporated in vacuo to give 43.0 mg of crude product. The crude product was placed on a column of silica gel and was eluted with 1:1 acetone-CH2C12. The isolated~product was crystallized from anhydrous methanol to afford 20.0 mg of the above-titled product m.pt 292-293°C
with dec.
Anal. Calcd. for C27H3503N~1/4 H2:
C,75:31;_H,8.25; N,3.25.
Found: C,75.49; H,8.29; N,3.45.
FAB: Calcd 422; Found 422.

Synthesis of 17-!3-(4-carboxymethylbenzoyl)-4-aza-5a-androst-1-en-3-one A. Oxi iQn_ 13.0 mg of the product from Example 25 was dissolved in 1 ml of glacial acetic acid. To the clear solution was added 10.0 mg of Cr03 (previously dried over P205 in vacuum at R.T.). Allowed the reaction tc progress overnight at R.T., and then at 0°C for 48 hours.. The addition of 7.0 ml of water caused the product to crystallize overnight in a refrigerator. The crude product was isolated, washed with cold eater and dried in a vacuum at 110°C below 1 mm pressv;re.
f - $6 _ The dried crude product was dissolved in IN
sodium hydroxide and the basic solution was extracted 3 times with. methylene chloride (The organic layers were separated, and the aqueous basic solution Was cooled and acidified with 1.5 N hydrochloric acid.
The precipitate was filtered, washed with water dried at 110°C under vacuum at 0.1 mm pressure.
Yield of above-titled product=7.0 mg.
to FAB Calc. C27E33C4N; 436; Found 436.

Synthesis of 17-13-(3,4-dihydroxybenzoyl)-4-aza-5a-androst-1-en-3-one A. Gri$narc~
To a suspension of 258.5 mg of dry activated magnesium chips in 10.0 ml of dry THF, was added 482 mQ. of 4-br~~mo-1,2-methylenedioxybenzene/N2. (The starting material i~s commercially available from Aldrich Che;aical) The reaction was conducted in an ultrasonic water bath at a temperature range of 2~°-30°C. To the well-agitated mixture was added 40 ~1 of 1,2-dibromoethane as a catalyst/N2, and the reaction was allowed to progress for 1 1/2-Z hours at 28°C/N2. The concentration of the formed Grignard reagent was 3.75 mmoles in 10 ml of dry THF.
The steroid from Example 2 (410 mg, lmmole) was suspended in 4.0 ml of dry THF/N2 and cooled to -80°C and 8.0 ml of the above-prepared Grignard (3.04 milliequivalents) was added via syringe to the steroidal suspension/N2 over a period of 5-10 minutes. T'he reaction was allowed to proceed for 1 a _8~_ hour at -80"C, and then at -10°C for an additional hour/N2. The reaction mixture was diluted with CH2C12, and then quenched with 1N HC1 at -5°C.
The organic layers were collected and washed with water 3 times, saturated NaCl solution 3 times, dried over MgS04, filtered and evaporated in vacuo to dryness. Purification of the crude product was carried out on 50.0 g of silica gel using as eluant l0 1:1(CH2C12-acetone) to give 347.0 mg.
FAB showed 422; Calcd. 422.
62.4 mg of the above product was crystallized from EtOAc to afford 11.39 mg~of product m.pt.324-325°C.
15 Anal. C;alcd. for C26H3104N .3/4 H20:
C,71.78; H,7.53; N,3.22.
Found: C,71.90; H,7.54; N,3.25.
FAB foi: C26H3104N showed 422; Calcd: 422.
20 B~ 1 v ~? of Methvlene DioxXlan Grouu 7() . 0 mg of the product from Step A was dissolved :in dry 25.0 ml of 1,2-dichloroethane at R.T./N2. 'the solution was allowed to cool to -10°C, and 1.03 m1 of BBr3 (1.0 M solution in 25 dichloromethane) was added dropwise under N2 atmosphere. The reaction Was allowed to proceed at R.T. for 3 1/2-4 hours/N2. After 4 hours/N2,, the reaction was cooled to (-10°C) and quenched with 10.0 ml of methanol for 10 minutes at 0°C, and then 3o gradually the temperature was allowed to rise to R.T.-/N2. The reaction mixture was evaporated in vacuo to dryness. The residue was extracted 3 times with EtOAc. The organic layers were washed with A

_ $$ -water 3 times, 2 times with saturated NaHC03 solution, 3 times with water and finally with a saturated solution of NaCl. The organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. The crude material was chromatographed on 2 silica gel plates, (20 cm x 20 cm x 20 cm x 250 E.~m) eluted with 1:1 (acetone -methylene chloride). Recrystallization from EtOAc afforded 5.0 mg of the above-titled product m.p.
222-222.5°C.
Anal. Calcd. for C25H3104N ~ 1/2 H20:
C,71.78; H,7.66; N,3.35.
Found: C,71.71; H,7.71; N,3.33.
FAB: Calcd. for C25H3104N~ 410; Found 410.
EXAMPLE 28~
Synthesis of 17-J3-(2 methoxybenzoyl)-4-aza-5a-androst-1-ene-3-one A. ri Tc a suspension of 258.0 mg of dry activated magnesium chips in 8.0 ml of dry THF was added 771.0 mg of o-bromoanisole in 2.0 ml of dry THF/N2. The reaction wa.s conducted in an ultrasonic water bath at a temperature range of 24-30°C. To the well-agitated mixture was added 30 ~.1 of 1,2-dibromoethane/N2, and the reaction was allowed to progress for 2 hours at 28°C/N2. The concentration of the formed Grignard reagent was 4 mmoles in 10.0 ml of dry THF.
- The steroid from Example 2 (205 mg, 0.5 mmoles) was' suspended in 2.0 ml of dry THF/N2, cooled to -79°C, a.nd 4.0 ml of the above-prepared Grignard A

_ 89 -(1.6 milli-equivalents) was added via syringe to the steroidal suspension/N2 over a period of 5-10 minutes. The reaction mixture was allowed to proceed for 1 hour at -80°C, and then at 0-2°C for an additional hour/N2. The reaction mixture was diluted with CH2C12 and then quenched with 1N HC1 solution at 0°C.
The organic layers were combined, washed 3 times with water, 3 times with saturated NaCl solution; and dried over MgS04. Filtered and evaporated in vacuum to dryness. The crude material was crystallized .from EtOAc to give 124.5 mg of product m.pt 228-230°C. Purification on silica gel column using 70:30 (CHC13-acetone) gave a single spot material in a yield of 83.0 mg m.pt. 241-241.5.
Anal. Calcd. for C26H3303N~
C,76.91; H,8.19; N,3.45 Found: C,76.36; H,8.26; N,3.35.
FAB calcd. for C26H33~3N~ 406; Found: 406.
B. Cleavage of Methoxv Group .
12.7 mg (0.03 mmoles) of the product from Step A was dissolved in 5.0 ml of dry methylene chloride/N2. To clear solution at -79°C/N, was added 50 ~1 of 1 mmole/ml of BBr3 in CH2C12 via syringe dropwise. Allowed the reaction to proceed at R.T. overnight/N2 with rapid stirring. Next day, a clear yellow solution was obtained. The reaction mixture was cooled to 0-2°C and quenched with water, to h3~dralyze excess of BBr3. The organic phase was washed 3 times with dilute sodium hydroxide, 3 times with water, 3 times with dilute HC1, 3 times with water, 3 times with saturated NaCI solution, and dried the organic layer over MgS04. Filtered, concentrated in a vacuum to dryness. The crude product crystallized from EtOAc to afford 7.0 mg ef a pure single spot material being 17-13-(Z-hydroxy-methyl-benzc~yl~-4-aza-5-a-androst-1-en-3-one.
FAB for C25H31N02~ Calcd: 394; Found: 394.

17f3(a-hvdroxvbenzvl)-4-aza-5a-androst-1-ene-3-one 570 milligrams of 1713-benzoyl-4-aza-5a-androst-1-ene-3-one (prepared from the thiopyridyl ester of Example 2 and commercially available phenyl magnesium bromide, analogously via the procedure in Example 5, to produce the 17-benzoyl derivative, mp.
295-296°C crystallized from EtOAc~ was suspended in 80 ml of anhydrous isopropanol. To the suspension was added 500.0 mg of NaBH4 in 5 portions. When all the hydride was added, 20.0 ml of dry THF was carefully added, so that the reaction mixture became a clear solution. Allowed the reaction to proceed at P,.T./N2 overnight. The reaction Was quenched carefully G~ith 1N HC1, and allowed to stir under N2 for an additional hour at R.T. It was then diluted with water,. and extracted 3 times with CHC13. The organic layers were combined, washed 3 times with H20; 3 time's With saturated NaCl solution, and dried over MgS04. Filtered and evaporated to a white solid weighing 4'5.0 mg.
_ The crude material was crystallized from EtOAc to a:Eford 349.5 mg of material. Further purificati~~n on a silica gel column, using as eluant, - 70:30 (CHC13-acetone) gave a single spot material, 221 mg, of the above-titled compound, m.pt 296-297°C.
Anal. Calcd. for C25H33N02:
C,79.17; H,8.78; N,3.70.
Found: C,79.24; H,8.85; N,3.48.
FAB Calcd. for C25H33N02: 380; Found: 380.

1713-h d~roxymethyl-4a~a-5a-androst-1-ene-3-one 500.0 mg of S-2-pyridyl-3-oxo-4-aza-5a-androst-1-ene-3 one (Example 2) was dissolved in 40.0 ml of dry THF at R.T./N2. The solution was cooled to -78°C/N2 and 5.5 ml of 1 M dibutyl aluminium hydride in THF was slowly added via syringe to the solution, with rapid stirring. Allowed the reaction to proceed _ at -76 to .-78°C for half an hour under N2. The temperature was gradually brought to R.T. and the reaction mixture kept f or 2-1/2 hours/N2. The reaction was then quenched at 0° to 5°C with 2N HC1 acid, and then diluted with CHC13. The organic layers were separated, washed with H20 3 times, then with saturated NaCl solution, and finally dried over MgS02. Filtered, and the organic phase was evaporated under vacuum to give 216.0 mg of crude product.
The crude product was chromatographed on 20.0 g of E.M. silica.gel column, using 70:30(CHC13-acetone ) a:; eluant .
'Meld of single spot material was 126.3 mg _ of the abo~~e-titled compound, m.pt. 271-271.5°C.
Calcd. for C19H2902N: FAB 304; Found 304.
NMR in CDC13 confirmed the above structure.
A

1713-Formyl-4-=aza-Sa-androst-1-ene-3-one Into a 100.0 ml dry flask was placed 1.3 ml of oxalyl ch:Loride (2 M in CH2C12) With 50.0 ml of dry CH2C1~/N2. The above solution Was cooled to -78°C and 33.3 ~1 of DMSO Was added dropwise via syringe/N2. The mixture Was stirred at -78°C/N2 for 30 minutes, .and a solution of above-prepared alcohol from Example 15, i.e. I7f3 hydroxymethyl-4-aza-5a-androst-1-ene-3-one (256.9 mg in 15.0 ml of dry CH2C12/N2 was added via syringe. The reaction was allowed to progress for one hour at -78°C/N2.
After an hour at -78°C, was added I ml of dry triethylamine at a rapid rate. Reaction was _raised slowly to R.T./N2 with stirring, the resulting yellow solution was then poured into 50.0 ml of cold water.
The organic layers were washed with a saturated solution of NaHC03, and then with a saturated solution of NaCl. Dried over MgS04, evaporated the solvent under vacuum to give 172.4 mg of crude product. Tree crude product was chromatogr.aphed on 60.0 g silica gel column using 70.30 (CHC13-acetone), to give a single spot material. Crystallization from EtOAc afforded the above-titled compound, 37.7 mg, m.pt. 258-2.'i9°C.

Synthesis o:E diastereoisomeric 1713(a-hydroxybenzyl)-4-aza-5a-androst-1-ene-3-ones - 26.3 of above-prepared formyl derivative (from Example 31) was dissolved in 7.0 ml of dry THF/N2. The solution was cooled to -78°C/N2, and 131 ~1 of phenyl magnesium bromide (Aldrich reagent) A

0.393 mill:iequivalents) in dry THF was added dropwise via syringE~/N2. Allowed the reaction to proceed for 1 hour/N2 at -78°C and then at R.T. for addition hour /N2 .
The reaction was quenched at 0-5°C with 2.5N
HC1, and then diluted with CHC13. Organic layers were separated, washed 3 times with water; 3 times with satur<~ted NaCl solution, dried over MgS04.
Filtered and evaporated in vacuum to dryness to afford 28.6 mg of crude product. Analysis of the NMR
spectra and peak heights from HPLC indicated this product to be a 1:1 mixture of diastereoisomers.
The crude :product was filtered through a 1 Eun Teflon filter and purified by HPLC on a Whitman Portisi1.10 column using 70:30(CHC13-acetone). The FAB mass spectrum indicated the same M++1 for both isomers, ' being 380 mass units. The faster eluting~isomer, m.pt. 289-289.5°C, was crystallized from EtOAc and showed a single spot material on TLC.
Anal. Calcd. for C25H33N02~1/4 H20;
C,78.39; H,8.81; N,3.65.
Found: C,78.11; H,8.65; N,3.58.
The slower eluting isomer, m.pt. 300-301°C
showed a single spot material on TLC. The f aster isomer showed by NMR(CDC13): CH3 at C-18 was deshielded.(0.898) as compared to the slower isomer , CH3 at C-18 at (0.69cS). The benzilic proton for the faster isomer was also deshielded (4.58) versus (4.958). 'The olefinic proton at C-1 showed deshielding effects for the faster isomer at (6.818) to (6.628). From the above data, the two isomers showed distinctly different physical properties.

Claims (25)

1. Use of a 17 .beta.-substituted 4-aza steroid, 5.alpha.-reductase inhibitor in conjunction with an .alpha.1-adrenergic receptor blocker in the treatment of benign prostatic hyperplasia.

2.of a 17 .beta.-substituted 4-aza steroid, 5.alpha.-reductase inhibitor and an .alpha.1-adrenergic receptor blocker in the manufacture of a medicament for the treatment of benign prostatic hyperplasia.

3. The use of claim 1 or 2, wherein said 5.alpha.-reductase inhibitor, 17.beta.-substituted 4-aza steroid is of the formula:

wherein:
the dotted line represents a double bond when present;
R1 and R3 are independently hydrogen, methyl or ethyl;

R2 is a hydrocarbon radical, selected from substituted or unsubstituted straight or branched chain alkyl, cycloalkyl, or aralkyl of from 1-12 carbons or monocyclic aryl optionally containing 1 or more lower alkyl substituents of from 1-2 carbon atoms and/or one or more halogen substituents;
R' is hydrogen or methyl;
R" is hydrogen or .beta.-methyl;
R "' is hydrogen, .alpha.-methyl or .beta.-methyl , or a pharmaceutically acceptable salt or ester thereof.

4. The use of claim 1 or 2, wherein said 17.beta.-substituted 4-aza steroid is of the formula:

wherein:
the dotted lane represents a double bond when present, and R is selected from hydrogen, methyl and ethyl; and R2 is(a) a monovalent radical selected from straight or branched chain alkyl, or cycloalkyl, of from 1-:12 carbons, which can be substituted by one or more of C1-C2 alkyl or halo;
(b) an aralkyl radical selected from benzyl or phenethyl;
(c) a polycyclic aromatic radical which can be substituted with one or more of: -OH;
protected -OH, -OC1-C4 alkyl, C1-C4 alkyl, halo or nitro;
(d) a monocyclic aromatic radical which can be substituted with one or more of:
(1) OH, -OC1-C4 alkyl, C1-C4 alkyl, - (CH2)m OH, - (CH2) n, COOH, including protected hydroxy, where m is 1-4, n is 1-3, providing C1-C4 alkyl is only present when one of the above oxygen-containing radicals is present;
(2) -SH, -SC1-C4 alkyl, -SOC1-C4 alkyl, -SO2C1-C4 alkyl, -SO2N(C1-C4-alkyl)2, C1-C4 alkyl - (CH2)m SH, -S- (CH2) n-O-COCH3, where m is 1-4, n is 1-3, providing C1-C4 alkyl is only present when one of the above sulfur containing radicals is present;
(3) N (R3) 2, which can be protected, where R3 is independently H or C1-C4 alkyl, where the monoaryl ring can also be further substituted with C1-C4 alkyl;
and (e) heterocyclic radical selected from 2- or 4-pyridyl, 2-pyrrolyl, 2-furyl or thiophenyl;
R', R" and R "' are each selected from hydrogen and methyl, or a pharmaceutically acceptable salt thereof.

5. The use of claim 1, 2, 3 or 4, wherein said al-adrenergic receptor blocker is selected from terazosin, doxazosin, prazosin, bunazosin, indoramin or alfuzosin.

6. The use of claim l, 2, 3 or 4, wherein said al-adrenergic receptor blocker is terazosin.

7. The use of claim 1 or 2, wherein said 17.beta.-substituted 4-aza steroid is finasteride and said .alpha.1-adrenergic receptor blocker is terazosin.

8. A pharmaceutical composition for the treatment of benign prostatic hyperplasia comprising a therapeutically effective amount of a 17.beta.-substituted 4-aza steroid, 5.alpha.-reductase inhibitor or a pharmaceutically acceptable ester or salt thereof and a therapeutically effective amount of an al-adrenergic receptor blocker, in a pharmaceutically acceptable carrier therefor.

9. A composition according to claim 8, wherein said 17.beta.-substituted 4-aza steroid is of the formula wherein:
the dotted line represents a double bond when present;
R1 and R3 are independently hydrogen, methyl or ethyl;
R2 is a hydrocarbon radical, selected from substituted or unsubstituted straight or branched chain alkyl, cycloalkyl, or aralkyl of from 1-12 carbons or monocyclic aryl optionally containing 1 or more lower alkyl substituents of from 1-2 carbon atoms and/or one or more halogen substituents;
R' is hydrogen or methyl;
R" is hydrogen or .beta.-methyl;
R'" is hydrogen, .alpha.-methyl or .beta.-methyl, or a pharmaceutically acceptable salt or ester thereof.

10. A composition according to claim 8, wherein said 17.beta.-substituted 4-azasteroid is of the formula wherein:

the dotted line represents a double bond when present, and R is selected from hydrogen, methyl and ethyl; and R2 is(a) a monovalent radical selected from straight or branched chain alkyl, or cycloalkyl, of from 1-12 carbons, which can be substituted by one or more of C1-C2 alkyl or halo;
(b) an aralkyl radical selected from benzyl or phenethyl;
(c) a polycyclic aromatic radical which can be substituted with one or more of: -OH;
protected -OH, -OC1-C4 alkyl , C1-C4 alkyl , halo or nitro;
(d) a monocyclic aromatic radical which can be substituted with one or more of:
(1) OH, -OC1-C4 alkyl, C1-C4 alkyl, - (CH2) mOH, - (CH2) n, COOH, including protected hydroxy, where m is 1-4, n is 1-3, providing C1-C4 alkyl is only present when one of the above oxygen-containing radicals is present;
(2) -SH, -SC1-C4 alkyl, -SOC1-C4 alkyl, -SO2C1-C4 alkyl, -SO2N(C,-C4-alkyl)2, C1-C4 alkyl - (CH2) mSH, -S- (CH2) n-O-COCH3, where m is 1-4, n is 1-3, providing C1-C4 alkyl is only present when one of the above sulfur containing radicals is present;
(3) N(R3)2, which can be protected, where R3 is independently H or C1-C4 alkyl, where the monoaryl ring can also be further substituted with C1-C4 alkyl;

and (e) heterocyclic radical selected from 2- or 4-pyridyl, 2-pyrrolyl, 2-furyl or thiophenyl;

R', R" and R"' are each selected from hydrogen and methyl, or a pharmaceutically acceptable salt thereof.

11. A composition according to claim 8, 9 or 10, wherein said .alpha.1-adrenergic receptor blocker is selected from terazosin, doxazosin, prazosin, bunarzosin, indoramin or alfuzosin.

12. A composition according to claim 8, 9, 10 or 11, wherein said .alpha.1,-adrenergic receptor blocker is terazosin.

13. A composition. according to claim 8, wherein said 17.beta. substituted 4-aza steroid is finasteride and said .alpha.1-adrenergic receptor blocker is terazosin.

14. A benign prostatic hyperplasia pharmaceutical combination comprising a therapeutically effective amount of a 17.beta.-substituted 4-aza steroid, 5.alpha.-reductase inhibitor and a therapeutically effective amount of an .alpha.1 adrenergic receptor blocker.

15. A combination according to claim 14, wherein said 17.beta.-substituted 4-aza steroid is of the formula wherein:
the dotted line represents a double bond when present;
R1 and R3 are independently hydrogen, methyl or ethyl;
R2 is a hydrocarbon radical, selected from substituted or unsubstituted straight or branched chain alkyl, cycloalkyl, or aralkyl of from 1-12 carbons or monocyclic aryl optionally containing 1 or more lower alkyl substituents of from 1-2 carbon atoms and/or one or more halogen substituents;
R' is hydrogen or methyl;
R" is hydrogen or .beta.-methyl;
R "' is hydrogen, .alpha.-methyl or .beta.-methyl, or a pharmaceutically acceptable salt or ester thereof.

16. A combination according to claim 14, wherein said 17.beta.-substituted 4-aza steroid is of the formula wherein:
the dotted line represents a double bond when present, and R is selected from hydrogen, methyl and ethyl; and R2 is(a) a monovalent radical selected from straight or branched chain alkyl, or cycloalkyl, of from 1-12 carbons, which can be substituted by one or more of Cl-C2 alkyl or halo;
(b) an aralkyl radical selected from benzyl or phenethyl;
(c) a ;polycyclic aromatic radical which can be substituted with one or more of: -OH;
protected -OH, -OC1-C4 alkyl, C1-C4 alkyl, halo or nitro;
(d) a monocyclic aromatic radical which can be substituted with one or more of:
(1) OH, -OC1-C4 alkyl , C1-C4 alkyl , - (CH2)mOH, - (CH2)n, COOH, including protected hydroxy, where m is 1-4, n is 1-3, providing C1-C4 alkyl is only present when one of the above oxygen-containing radicals is present;

(2) -SH, -SC1-C4 alkyl, -SOC1-C4 alkyl, -SO2C1-C4 alkyl, -SO2N (C1-C4-alkyl) 2, C1-C4 alkyl - ( CH2 ) mSH, -S- ( CH2 ) n-O-COCH3, where m is 1-4, n is 1-3, providing C1-C4 alkyl is only present when one of the above sulfur containing radicals is present;
(3) N(R3)2, which can be protected, where R3 is independently H or C1-C4 alkyl, where the monoaryl ring can also be further substituted with C1-C9 alkyl;
and (e) heterocyclic radical selected from 2- or 4-pyridyl, 2-pyrrolyl, 2-furyl or thiophenyl;
R', R" and R "' are each selected from hydrogen and methyl, or a pharmaceutically acceptable salt thereof.

17. A combination according to claim 14, 15 or 16, wherein said .alpha.1-adrenergic receptor blocker is selected from terazosin, doxazosin, prazosin, bunazosin, indoramin or alfuzosin.

18. A combination according to claim 14, 15 or 16, wherein said .alpha.1-adrenergic receptor blocker is terazosin.

19. A combination according to claim 14, wherein 173-substituted 4-azasteroid is finasteride and said .alpha.1-adrenergic receptor blocker is terazosin.

20. The use of claim 1, 2, 3 or 4, wherein said .alpha.1-adrenergic receptor blocker is doxazosin.

21. The use of claim 1 or 2, wherein said 17.beta.-substituted 4-aza steroid is finasteride and said .alpha.1-adrenergic receptor blocker is doxazosin.

22. A composition according to claim 8, 9, 10 or 11, wherein said .alpha.1-adrenergic receptor blocker is doxazosin.

23. A composition according to claim 8, wherein said 17.beta. substituted 4-azasteroid is finasteride and said .alpha.1-adrenergic receptor blocker is doxazosin.

24. A combination according to claim 14, 15 or 16, wherein said .alpha.1-adrenergic receptor blocker is doxazosin.

25. A combination according to claim 14, wherein said 17.beta.-substituted 4-azasteroid is finasteride and said .alpha.1-adrenergic receptor blocker is doxazosin.